Spiro-oxazolones

ABSTRACT

The present invention provides spiro-oxazolones, which act as V1a receptor modulators, and in particular as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The present compounds are useful as therapeutics acting peripherally and centrally in the conditions of inappropriate secretion of vasopressin, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, aggressive behavior and phase shift sleep disorders, in particular jetlag.

The present invention provides spiro-oxazolones, which act as V1areceptor modulators, and in particular as V1a receptor antagonists,their manufacture, pharmaceutical compositions containing them and theiruse as medicaments. The present compounds are useful as therapeuticsacting peripherally and centrally in the conditions of inappropriatesecretion of vasopressin, anxiety, depressive disorders, obsessivecompulsive disorder, autistic spectrum disorders, schizophrenia,aggressive behavior and phase shift sleep disorders, in particularjetlag.

TECHNICAL FIELD

The present invention provides a compound of formula I,

wherein the substituents and variables are as described below and in theclaims, or a pharmaceutically acceptable salt thereof.

The present compounds are V1a receptor antagonists, useful for thetreatment of autistic spectrum disorders.

BACKGROUND ART

Three vasopressin receptors, all belonging to the class I G-proteincoupled receptors, are known. The V1a receptor is expressed in thebrain, liver, vascular smooth muscle, lung, uterus and testis, the V1bor V3 receptor is expressed in the brain and pituitary gland, the V2receptor is expressed in the kidney where it regulates waterreabsorption and mediates the antidiuretic effects of vasopressin(Robben, et al.)¹. Compounds with activity at the V2 receptor maytherefore cause side-effects on blood homeostasis.

The oxytocin receptor is related to the Vasopressin receptor family andmediates the effects of the neurohormone oxytocin in the brain and theperiphery. Oxytocin is believed to have central anxiolytic effects(Neumann)². Central oxytocin receptor antagonism might therefore lead toanxiogenic effects, which are regarded as undesired side-effects.

In the brain vasopressin acts as a neuromodulator and is elevated in theamygdala during stress (Ebner, et al.)³. It is known that stressful lifeevents can trigger major depression and anxiety (Kendler, et al.)⁴ andthat both have very high comorbidity, with anxiety often preceding majordepression (Regier, et al.)⁵. The V1a receptor is extensively expressedin the brain and particularly in limbic areas like the amygdala, lateralseptum and hippocampus which are playing an important role in theregulation of anxiety. Indeed V1a knock-out mice show a reduction inanxious behavior in the plus-maze, open field and light-dark box(Bielsky, et al.)⁶. The down-regulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxious behavior (Landgraf, et al.)⁷. Vasopressin or theV1a receptor are also implicated in other neuropsychological disorders:genetic studies linked sequence polymorphism in the promoter of thehuman V1a receptor to autistic spectrum disorders (Yirmiya, et al.)⁸,intranasal administration of vasopressin was shown to influenceaggression in human males (Thompson, et al.)⁹ and vasopressin levelswere found to be elevated in schizophrenic patients (Raskind, et al.)¹⁰and patients with obsessive-compulsive disorder (Altemus, et al.)¹¹.

Autistic Spectrum Disorders (ASD) are a clinically heterogeneouscondition characterized by defects in socialization and language. ASDinclude a wide range of abnormalities including a genuine incapacity toorganize affective relations, behavioral anomalies in reciprocal socialinteractions, verbal and non-verbal communication, limited interest inthe surrounding environment associated with stereotyped movements andrepetitive plays (Bourreau et al, 2009)¹². Research to date indicatesthat a genetic predisposition may be involved, but also environmentalfactors have to be taken into consideration (Bourgeron, 2009)¹³. Thereis at present no efficient biological/pharmaceutical treatment to ASD.

The suprachiasmatic nucleus (SCN) is the endogenous clock of the bodyregulating circadian rhythmicity and is known to be rich in vasopressinneurons (Kalsbeek et al. 2010)¹⁴, producing and releasing vasopressinwith a 24 h circadian rhythm (Schwartz et al. 1983)¹⁵. A majorregulatory effect of vasopressin on circadian rhythm could not bedemonstrated by the prior art. The Brattleboro rat, a rat strainnaturally lacking vasopressin due to a point mutation, has no obviousdefect in its circadian rhythm (Groblewski et al. 1981)¹⁶. Injection ofvasopressin directly in the hamster SCN had no effect on circadian phaseshift (Albers et al. 1984)¹⁷. In contrast, the vasopressin receptorswere shown to modulate the circadian clock in a more subtle way.Yamaguchi et at (2013)¹⁸ demonstrated that V1a knock-out and V1a/V1bdouble knock-out mice show faster reentrainment to the new light/darkcycle after a circadian phase advance or a phase delay, an experimentmimicking jet-lag in humans. The same result was obtained after chronicadministration of a mixture of V1a and V1b small molecule antagoniststhrough a minipump directly on the SCN.

DETAILED DESCRIPTION OF THE INVENTION

Object of the present invention is a compound of formula I and theirpharmaceutically acceptable salts thereof, the preparation of the abovementioned compounds, medicaments containing them and their manufactureas well as the use of the above mentioned compounds in the therapeuticand/or prophylactic treatment of diseases and disorders which areassociated with modulation of the V1a receptor, and in particular withV1a receptor antagonism. A further object of the invention is to provideselective inhibitors of the V1a receptor, since selectivity for the V1areceptor is expected to afford a low potential to cause unwantedoff-target related side effects such as discussed above.

The following definitions of the general terms used in the presentdescription apply irrespectively of whether the terms in question appearalone or in combination with other groups.

The term “C₁₋₆-alkyl”, alone or in combination with other groups, standsfor a hydrocarbon radical which may be linear or branched, with singleor multiple branching, wherein the alkyl group in general comprises 1 to6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl(i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl(tert-butyl), isopentyl, 2-ethyl-propyl, 1,2-dimethyl-propyl and thelike. Particular “C₁₋₆-alkyl” groups have 1 to 4 carbon atoms(“C₁₋₄-alkyl”). A specific group is methyl.

The term “halogen-C₁₋₆-alkyl”, alone or in combination with othergroups, refers to C₁₋₆-alkyl as defined herein, which is substituted byone or multiple halogen, in particular 1-5 halogen, more particular 1-3halogen (“halogen-C₁₋₃-alkyl”), specific 1 halogen or 3 halogen.Particular halogen is fluoro. Particular “halogen-C₁₋₆-alkyl” is“fluoro-C₁₋₆-alkyl”. Examples are CH₂F, CHF₂ and CF₃.

The term “hydroxy”, alone or in combination with other groups, refers toOH.

The term “halogen”, alone or in combination with other groups, denoteschloro (Cl), iodo (I), fluoro (F) and bromo (Br).

The term “C₁₋₆-alkoxy”, alone or in combination with other groups,stands for an —O—C₁₋₆-alkyl radical which may be linear or branched,with single or multiple branching, wherein the alkyl group in generalcomprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy(OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy),2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy(i-pentyloxy) and the like. Particular “C₁₋₆-alkoxy” groups have 1 to 4carbon atoms (“C₁₋₄-alkoxy”). A specific group is OMe.

The term “pharmaceutically acceptable salts” refers to salts that aresuitable for use in contact with the tissues of humans and animals.Examples of suitable salts with inorganic and organic acids are, but arenot limited to acetic acid, citric acid, formic acid, fumaric acid,hydrochloric acid, lactic acid, maleic acid, malic acid,methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonicacid, succinic acid, sulfuric acid, sulphuric acid, tartaric acid,trifluoroacetic acid and the like. Particular acids are formic acid,trifluoroacetic acid and hydrochloric acid. Particular are hydrochloricacid, trifluoroacetic acid and fumaric acid.

The terms “pharmaceutically acceptable carrier” and “pharmaceuticallyacceptable auxiliary substance” refer to carriers and auxiliarysubstances such as diluents or excipients that are compatible with theother ingredients of the formulation.

The term “pharmaceutical composition” encompasses a product comprisingspecified ingredients in pre-determined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. In particular it encompassesa product comprising one or more active ingredients, and an optionalcarrier comprising inert ingredients, as well as any product thatresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

The term “half maximal inhibitory concentration” (IC₅₀) denotes theconcentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC₅₀ values can beconverted logarithmically to pIC₅₀ values (−log IC₅₀), in which highervalues indicate exponentially greater potency. The IC₅₀ value is not anabsolute value but depends on experimental conditions e.g.concentrations employed. The IC₅₀ value can be converted to an absoluteinhibition constant (Ki) using the Cheng-Prusoff equation (Biochem.Pharmacol. (1973) 22:3099). The term “inhibition constant” (Ki) denotesthe absolute binding affinity of a particular inhibitor to a receptor.It is measured using competition binding assays and is equal to theconcentration where the particular inhibitor would occupy 50% of thereceptors if no competing ligand (e.g. a radioligand) was present. Kivalues can be converted logarithmically to pK_(i) values (−log K_(i)),in which higher values indicate exponentially greater potency.

The term “antagonist” denotes a compound that diminishes or prevents theaction of another compound as defined e.g. in Goodman and Gilman's “ThePharmacological Basis of Therapeutics, 7th ed.” in page 35, MacmillanPubl. Company, Canada, 1985. In particular, antagonists refer to acompound that attenuates the effect of an agonist. A “competitiveantagonist” binds to the same site of a receptor as the agonist but doesnot activate the receptor, thus blocks the agonist's action. A“non-competitive antagonist” binds to an allosteric (non-agonist) siteon the receptor to prevent activation of the receptor. A “reversibleantagonist” binds non-covalently to the receptor, therefore can be“washed out”. An “irreversible antagonist” binds covalently to thereceptor and cannot be displaced by either competing ligands or washing.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The term “as defined herein” and “as described herein” when referring toa variable incorporates by reference the broad definition of thevariable as well as preferred, more preferred and most preferreddefinitions, if any.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC¹⁹.

The term “pharmaceutically acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

The terms “Autistic Spectrum” and “Autistic Spectrum Disorders”summarize conditions classified as pervasive developmental disorders,which include but are not limited to autism, Asperger syndrome,pervasive developmental disorder not otherwise specified (PDD-NOS),childhood disintegrative disorder, Rett syndrome and Fragile X, inparticular autism. These disorders are typically characterized by socialdeficits, communication difficulties, stereotyped or repetitivebehaviors and interests, and cognitive delays.

The term “phase shift sleep disorders” summarizes conditions classifiedas disturbances in the circadian rhythm, i.e. the approximately 24-hourcycles that are generated by an organism, e.g. a human being. Phaseshift sleep disorders include, but are not limited to transientdisorders like jetlag or a changed sleep schedule due to work, socialresponsibilities, or illness, as well as chronic disorders like delayedsleep-phase syndrome (DSPS), delayed sleep-phase type (DSPT), advancedsleep-phase syndrome (ASPS), and irregular sleep-wake cycle.

The phrase “whereby only one of X¹, X², X³ and X⁴ is N” mean thatmaximal one of X¹⁻⁴ is N and the remaining residues are eachindividually C—R¹, or that all X¹⁻⁴ are each individually C—R¹.

The phrase “whereby only one of Y¹, Y², Y³ and Y⁴ is N” mean thatmaximal one of Y¹⁻⁴ is N and the remaining residues are eachindividually C—R⁴, or that all Y¹⁻⁴ are each individually C—R⁴.

In detail, the present invention provides compounds of the generalformula I

wherein

-   X¹ is C—R¹ or N;-   X² is C—R¹ or N;-   X³ is C—R¹ or N;-   X⁴ is C—R¹ or N;    whereby only one of X¹, X², X³ and X⁴ is N;-   R¹ each separately is selected from the group consisting of    hydrogen, halogen, hydroxy, C₁₋₆-alkyl and C₁₋₆-alkoxy;-   R² is selected from the group consisting of H and C₁₋₆-alkyl;-   R³ is selected from the group consisting of H and C₁₋₆-alkyl;-   or R² and R³ together are ═O;-   Y¹ is C—R⁴ or N;-   Y² is C—R⁴ or N;-   Y³ is C—R⁴ or N;-   Y⁴ is C—R⁴ or N;    whereby only one of Y¹, Y², Y³ and Y⁴ is N;-   R⁴ each separately is selected from the group consisting of    hydrogen, halogen, halogen-C₁₋₆-alkyl, hydroxy, C₁₋₆-alkyl,    C₁₋₆-alkoxy and Si(C₁₋₆-alkyl)₃;-   m is 1, 2 or 3; and-   n is 0 or 1;    or pharmaceutically acceptable salts thereof.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein

-   X¹ is C—H or N;-   X² is C—R¹ or N;-   X³ is C—R¹;-   X⁴ is C—H or N;    whereby only one of X¹, X², X³ and X⁴ is N;-   R¹ each separately is selected from the group consisting of    hydrogen, halogen, hydroxy, and C₁₋₆-alkyl;-   R² is selected from the group consisting of H and C₁₋₆-alkyl;-   R³ is selected from the group consisting of H and C₁₋₆-alkyl;-   or R² and R³ together are ═O;-   Y¹ is C—H or N;-   Y² is C—R⁴ or N;-   Y³ is C—R⁴ or N;-   Y⁴ is C—H or N;    whereby only one of Y¹, Y², Y³ and Y⁴ is N;-   R⁴ each separately is selected from the group consisting of    hydrogen, halogen, hydroxy and C₁₋₆-alkyl;-   m is 1; and-   n is 1.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein

X¹, X², X³ and X⁴ are each CH;

-   R² is selected from the group consisting of H and C₁₋₆-alkyl;-   R³ is selected from the group consisting of H and C₁₋₆-alkyl;-   or R² and R³ together are ═O;

m and n are each 1;

Y¹ and Y⁴ are each CH; and

Y² and Y³ are each CF.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein

X¹, X², X³ and X⁴ are each CH;

R² and R³ are each H;

m and n are each 1;

Y¹ and Y⁴ are each CH; and

Y² and Y³ are each CF.

A certain embodiment of this invention refers to an intermediate of acompound of formula I as described herein, wherein

-   X¹ is C—R¹;-   X² is C—R¹;-   X³ is C—R¹;-   X⁴ is C—R¹ or NO;-   R¹ each separately is selected from the group consisting of    hydrogen, halogen, hydroxy, C₁₋₆-alkyl and C₁₋₆-alkoxy;-   R² is selected from the group consisting of H and C₁₋₆-alkyl;-   R³ is selected from the group consisting of H and C₁₋₆-alkyl;-   or R² and R³ together are ═O;-   Y¹ is C—R⁴ or N;-   Y² is C—R⁴ or N;-   Y³ is C—R⁴ or N;-   Y⁴ is C—R⁴ or N;    whereby only one of Y¹, Y², Y³ and Y⁴ is N;-   R⁴ each separately is selected from the group consisting of    hydrogen, halogen, halogen-C₁₋₆-alkyl, hydroxy, C₁₋₆-alkyl,    C₁₋₆-alkoxy and Si(C₁₋₆-alkyl)₃;-   m is 1, 2 or 3; and-   n is 0 or 1;    or pharmaceutically acceptable salts thereof.

A certain embodiment of this invention refers to an intermediate of acompound of formula I as described herein, wherein

X¹, X² and X³ are each CH and X⁴ is NO;

R² and R³ are each C₁₋₆-alkyl;

m and n are each 1; and

Y¹, Y², Y³ and Y⁴ are each CH.

A certain embodiment of this invention refers to an intermediate of acompound of formula I as described herein, wherein

X¹, X² and X³ are each CH and X⁴ is NO;

R² and R³ are each H;

m and n are each 1; and

Y¹, Y², Y³ and Y⁴ are each CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹ is CH, or C-halogen.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹ is CH, C—Cl or C—F.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹ is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X² is CH, C-halogen, C—C₁₋₆-alkyl,C—C₁₋₆-alkoxy or C—OH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X² is CH, C—Cl, C—CH₃, C—OCH₃ or C—OH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X² is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X³ is CH, C-halogen, C—C₁₋₆-alkyl,C—C₁₋₆-alkoxy or C—OH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X³ is CH, C—Br, C—Cl, C—F, C—CH₃, C—OCH₃ orC—OH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X³ is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X⁴ is CH, C-halogen or C—C₁₋₆-alkyl.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X⁴ is CH, C-Me or C—F.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X⁴ is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹, X², X³ and X⁴ are each CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X², X³ and X⁴ are each CH and X¹ is N.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹, X³ and X⁴ are each CH and X² is N.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹, X² and X⁴ are each CH and X³ is N.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹, X² and X³ are each CH and X⁴ is N.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R² is H or C₁₋₆-alkyl.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R² is H or Me.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R² is H.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R³ is H or C₁₋₆-alkyl.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R³ is H or Me.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R³ is H.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein R² and R³ together are ═O.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein m is 1 and n is 0 or 1.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein m is 1 and n is 1.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein m is 2 and n is 0 or 1.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein m is 3 and n is 0.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y¹ is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y² is CH, C-halogen, C—C₁₋₆-alkyl,C—C₁₋₆-alkoxy or C—OH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y² is CH, C—F, C—CH₃, C—OCH₃ or C—OH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y² is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y³ is CH, C-halogen, C-halogen-C₁₋₆-alkyl,C—C₁₋₆-alkyl, C—C₁₋₆-alkoxy, C—OH or Si(C₁₋₆-alkyl)₃.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y³ is CH, C—CH₂Cl, C—CH₂F, C—CHF₂, C—Cl,C—F, C—CH₃, C—OCH₃, C—OH or C—Si(CH₃)₃.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y³ is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y⁴ is CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y¹, Y², Y³ and Y⁴ are each CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein Y¹, Y³ and Y⁴ are each CH and Y² is N.

A certain embodiment of this invention refers to a compound of formula Ias described herein, wherein X¹, X² and X³ are each CH and X⁴ is N, R²and R³ are each C₁₋₆-alkyl, R² and R³ are each C₁₋₆-alkyl, m and n areeach 1 and Y¹, Y², Y³ and Y⁴ are each CH.

A certain embodiment of this invention refers to a compound of formula Ias described herein, selected from the group consisting of

-   (1R)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,-   (1S)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,-   1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl)-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(4′-oxo-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dimethoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dimethyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-methoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-[(2R)-4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-[(2R)-5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-[(2S)-4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-[(2S)-5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3-(trifluoromethyl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[b]pyridine-6,5′-[1,3]oxazol]-4′-one,-   2′-(2-hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(2-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(2-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3,3-dimethyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(4-methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(5,5-dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(6-methyl-1′H,3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1-oxido-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,-   2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,-   2′-spiro[5H-furo[3,4-b]pyridine-7,4′-piperidine]-1′-ylspiro[indane-2,5′-oxazole]-4′-one,-   2′-spiro[7H-furo[3,4-b]pyridine-5,4′-piperidine]-1′-ylspiro[indane-2,5′-oxazole]-4′-one,-   3-(chloromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   3-(difluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   3-(fluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,-   3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,-   3-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   4-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,-   4-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   4-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5,6-dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5,6-dimethoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5,6-dimethyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5-bromo-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-chloro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-fluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,-   6-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one,    and-   7-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one.

A certain embodiment of this invention refers to a compound of formula Ias described herein, selected from the group consisting of

-   (+)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,-   (−)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,-   1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl)-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(4′-oxo-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dimethoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dimethyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-methoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-[4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one    enantiomer A,-   1′-[4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one    enantiomer B,-   (−)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   (+)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3-(trifluoromethyl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[b]pyridine-6,5′-[1,3]oxazol]-4′-one,-   2′-(2-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(2-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3,3-dimethyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(4-methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(5,5-dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(6-methyl-1′H,3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,-   2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,-   2′-(1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   3-(chloromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   3-(difluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   3-(fluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,-   3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,-   3-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,-   4-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,-   4-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   4-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5,6-dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5,6-dimethoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5,6-dimethyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5-bromo-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-chloro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-fluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,-   6-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one,    and-   7-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one.

A certain embodiment of this invention refers to a compound of formula Ias described herein, selected from the group consisting of

-   1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5,6-dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(5-hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-[(2R)-5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(5,5-dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,-   3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,-   5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   5,6-dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,    and-   6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one.

A certain embodiment of this invention refers to a compound of formula Ias described herein, selected from the group consisting of

-   2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,-   2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,    and-   2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one.

A certain embodiment of this invention refers to a compound of formula Ias described herein that is2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one.

A certain embodiment of this invention refers to a compound of formula Ias described herein that is5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one.

A certain embodiment of this invention refers to a compound of formula Ias described herein that is2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one.

In a certain embodiment, the invention relates to a process tomanufacture a compound of formula (I) comprising the step of reacting acompound of formula (II)

with a compound of formula (III)

wherein n, m, R², R³, X¹⁻⁴ and Y¹⁻⁴ are as defined hereinabove forformula (I).

A certain embodiment of this invention refers to a compound of formula Ias described herein, whenever prepared by a process as defined herein.

A certain embodiment of this invention refers to a compound of formula Ias described herein for use as therapeutically active substance.

A certain embodiment of this invention refers to a compound of formula Ias described herein for the use as therapeutically active substance forthe therapeutic and/or prophylactic treatment of diseases and disorderswhich are associated with Via receptor antagonism.

A certain embodiment of this invention refers to a compound of formula Ias described herein for the use as therapeutically active substanceacting peripherally and centrally in the conditions of inappropriatesecretion of vasopressin, anxiety, depressive disorders, obsessivecompulsive disorder, autistic spectrum disorders, schizophrenia,aggressive behavior and phase shift sleep disorders, in particularjetlag.

A certain embodiment of this invention refers to a pharmaceuticalcomposition comprising a compound of formula I as described herein and apharmaceutically acceptable carrier and/or a pharmaceutically acceptableauxiliary substance.

A certain embodiment of this invention refers to the use of a compoundof formula I as described herein for the manufacture of a medicament foracting peripherally and centrally in the conditions of inappropriatesecretion of vasopressin, anxiety, depressive disorders, obsessivecompulsive disorder, autistic spectrum disorders, schizophrenia,aggressive behavior and phase shift sleep disorders, in particularjetlag.

A certain embodiment of this invention refers to a method for the use ofa compound as described herein, which is acting peripherally andcentrally in the conditions of inappropriate secretion of vasopressin,anxiety, depressive disorders, obsessive compulsive disorder, autisticspectrum disorders, schizophrenia, aggressive behavior and phase shiftsleep disorders, in particular jetlag, which method comprisesadministering said compound of formula I to a human being or animal.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as their solvates ofthe compounds of formula I.

The compounds of formula I may contain one or more asymmetric centersand can therefore occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centrewill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within this invention.The present invention is meant to encompass all such isomeric forms ofthese compounds. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccentre of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography.

Compounds of formula 1 can be prepared according to the followingprocesses.

The processes are described in more detail with the following generalschemes A to H and general procedures I to XXIII.

Compounds of formula (I) can be prepared by thermal condensation of asecondary amine of formula (II) and an 2-amino-oxazol-4-one of formula(III). Secondary amines of formula (II) are either commerciallyavailable or can be prepared by methods known in the art or describedhereinafter. 2-Amino-oxazol-4-ones of formula (III) can be prepared bymethods known in the art or described hereinafter. The syntheses ofcompounds of formulas (II) and (III) are outlined in general schemes Dto I hereinafter. General scheme 1 is hereinafter further illustrated bygeneral procedure XXI.

Compounds of formula (V) can be prepared by reaction of a secondaryamine of formula (II) and chloroacetyl isocyanate (IV) indichloromethane and subsequently treatment of the urea-intermediate with1,8-diazabicyclo[5.4.0]undec-7-ene in tetrahydrofuran at roomtemperature.

Compounds of formula (VII) and (VIII) can be prepared from compounds offormula (V) according to methods known in the art, e.g. by consecutivelytreating a compound of formula (V) with an organic base such as lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide and3-bromoprop-1-yne (VI). Compounds of formula (I-a) can be prepared bycyclization of a compound of formula (VIII) with alkynes of formula (IX)in a solvent such as 1,2-dichloroethane using a catalyst such aschloro(pentamethyl-cyclopentadienyl)(cyclooctadiene)ruthenium(II), attemperatures between 0° C. and 75° C. Compounds of formula (XI) can beprepared from compounds of formula (VII) according to methods known inthe art, e.g. by consecutively treating a compound of formula (VII) withan organic base such as lithium diisopropylamide or lithiumbis(trimethylsilyl)amide and bromoacetonitrile (X). Compounds of formula(I-b) can be prepared by cyclization of a compound of formula (XI) withalkynes of formula (IX) in a solvent such as toluene using a catalystsuch as cyclopentadienylcobalt dicarbonyl at temperatures between 0° C.and 75° C. General scheme 3 is hereinafter further illustrated bygeneral procedures XXII and XXIII.

2-Amino-oxazol-4-one intermediates of formula (III) can be prepared bycyclization of an alpha-hydroxy ester of formula (XII) with guanidiniumhydrochloride (XIII) in an alcohol such as tert-butanol using a basesuch as potassium tert-butoxide and a drying agent such as molecularsieves 4A. General scheme 4 is hereinafter further illustrated bygeneral procedure XX.

Alpha-hydroxy ester intermediates of formula (XII) can be prepared bytreatment of cyanohydrin intermediates of formula (XV), (XVI) or amixture of both, which are prepared according to methods and startingmaterials well known in the art, under standard conditions like stirringin a mixture of a solvent like methanol or ethanol and concentratedhydrochloric acid. Alternatively, intermediates of formula (XII) can beobtained by treatment of a compound of formula (XV), (XVI) or a mixtureof both under Pinner type conditions followed by treatment of theimidate intermediate with water. Cyanohydrins of formula (XV) or (XVI)can be prepared by methods and starting materials well known in the art,e.g. by treating a ketone of formula (XIV) with trimethylsilyl cyanidein dichloromethane at room temperature using a catalyst such as coppertriflate. Alternatively intermediates of formula (XV) can be prepared bytreatment of a ketone of formula (XIV) with acetone cyanohydrin in asolvent such as tetrahydrofuran at room temperature using a catalystsuch as lanthanum(III)triisopropoxide or with hydrogen cyanide, whichcan be prepared in situ from a cyanide salt such as potassium or sodiumcyanide and an acid such as hydrochloric acid. Alpha-hydroxy acidintermediates of formula (XVII) can be prepared by treating acyanohydrin of formula (XV), (XVI) or a mixture of both in an acid suchas concentrated hydrochloric acid. Alpha-hydroxy ester intermediates offormula (XII) can be prepared by treatment of an alpha-hydroxy acidintermediate of formula (XVII) by esterification in an alcohol such asmethanol or ethanol and a catalytic amount of an acid such asconcentrated sulfuric acid. General scheme 5 is hereinafter furtherillustrated by general procedures XV to XVIII.

Malonic acid di-ester intermediates of formula (XX) can be prepared byalkylation of a commercially available malonic ester with anintermediate of formula (XIX) (wherein LG is a leaving group likehalogen or sulfonyl), which is commercially available or prepared bymethods known in the art. A malonic acid mono-ester intermediate offormula (XXI) can be prepared by deprotection of an intermediate offormula (XX) by methods known in the art, such as treatment withtrifluroacetic acid in dichloromethane at room temperature.Indan-2-carboxylic acid intermediates of formula (XXII) are prepared bydecarboxylation of intermediates of formula (XXI) in a solvent likedimethylsulfoxide in the presence of water and lithium chloride at 180°C. Alpha-hydroxy ester intermediates of formula (XII) can be obtained bytreatment of an intermediate of formula (XXII) with a base like lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide in a solvent suchas tetrahydrofuran followed by alpha-hydroxylation with camphorsulfonyloxaziridine. General scheme 6 is hereinafter further illustrated bygeneral procedures XIII, XIV and XIX.

Indan-2-one intermediates of formula (XIV) can be obtained by Rhodiumcatalyzed intramolecular cyclization of a diazo ketone intermediate offormula (XXIV), which can be prepared by treatment of an acid chlorideof formula (XXIII) with trimethylsilyl diazomethane in acetonitrile at0° C. General scheme 7 is hereinafter further illustrated by generalprocedure X.

Amine intermediates of formula (II) can be prepared as describedhereinafter: Cross coupling reaction of an aromatic halide of formula(XXV), which is commercially available or prepared by methods known inthe art, with a boronic acid ester of formula (XXVI) in the presence ofa palladium catalyst, e.g. formed in situ from palladium acetate andtriphenylphosphine, and an inorganic base such as potassium carbonategives a tetrahydropyridine derivative of formula (XXVII). Compounds offormula (XXVII) can be cyclized with iodine and silver(I)oxide in a1,4-dioxane/water mixture or with iodine and potassium iodide in awater/acetonitrile mixture to give spiro iodo-piperidines of formula(XXVIII). Compounds of formula (XXIX) can be obtained underhydrogenolytic conditions, e.g. using hydrogen gas in the presence ofpalladium on charcoal and an organic base such as triethyl amine, orusing tri-n-butyltin hydride and a radical starter such asazobisisobutyronitrile. N-BOC-deprotection of compounds of formula(XXIX) under acidic conditions, e.g. hydrogen chloride in 1,4-dioxane ortrifluoroacetic acid in dichloromethane, gives amine intermediates offormula (II). General scheme 8 is hereinafter further illustrated bygeneral procedures I to IV and VIII to IX.

Amine intermediates of formulas (II), (II-a) and (II-b) can be preparedas described hereinafter: Double-lithiation of a 2-bromobenzoic acidderivative of formula (XXXIII) via deprotonation and bromine-lithiumexchange with an alkyllithium reagent and subsequent addition to1-benzylpiperidin-4-one (XXX) leads to a spirolactone derivative offormula (XXXIV). Compounds of formula (XXXIV) can be reduced eitherdirectly with borane or using a stepwise procedure by consecutivetreatment with diisopropylaluminum hydride, acetic anhydride in thepresence of pyridine and 4-(N,N-dimethylamino)-pyridine, andtriethylsilane in the presence of boron trifluoride to yield compoundsof formula (XXXVII). Double-metallation of a 2-bromoaryl substitutedbenzylic alcohol derivative of formula (XXXV), which is commerciallyavailable or prepared by methods known in the art, via O-deprotonationand bromine-metal exchange with magnesium, or a Grignard or alkyllithiumreagent, and subsequent addition to 1-benzylpiperidin-4-one (XXX) leadsto a diol derivative of formula (XXXVI). Cyclization of the diolderivatives of formula (XXXVI) with methanesulfonyl chloride using abase such as triethylamine leads to spiro derivatives of formula(XXXVII). Treatment of compounds of formula (XXXI), which arecommercially available or prepared by methods known in the art, withisopropyl magnesium chloride leads to the formation of a Grignardreagent which is added to the carbonyl moiety of 1-benzylpiperidin-4-one(XXX) to form compounds of formula (XXXII). Treatment of a compound offormula (XXXII) with carbon monoxide in the presence of a palladiumcatalyst e.g. formed in situ from palladium acetate andtriphenylphosphine, and an amine base to form spirolactone compounds offormula (XXXIV). Amine derivatives of formulas (II), (II-a) and (II-b)are obtained by palladium-catalyzed hydrogenolytic N-debenzylation ofcompounds of formulas (XXXIV) and (XXXVII), respectively. General scheme9 is hereinafter further illustrated by general procedures VI to VII.

Compounds of formula (I-d) and (I-e) can be prepared as describedhereinafter: An N-oxide intermediate of formula (XXXVIII) can beobtained by treatment of a compound of formula (I-c) with a suitableoxidizing agent such as m-chloroperbenzoic acid in a suitable solventsuch as dichloromethane at room temperature. An N-oxide intermediate offormula (XXXVIII) can consequently be heated in excess acetic anhydridein the presence of 2,4,6-trimethylpyridine followed by treatment with acatalytic amount of sodium methoxide in methanol at room temperature togive a mixture of a compound of formula (I-d) and a compound of formula(I-e), which can be separated by a suitable method such aschromatography or crystallization. Alternatively, the O-acetylatedprecursors of compounds of formula (I-d) and (I-e) can be can beseparated by a suitable method such as chromatography or crystallizationprior to treatment with sodium methoxide in methanol.

The corresponding pharmaceutically acceptable salts with acids can beobtained by standard methods known to the person skilled in the art,e.g. by dissolving the compound of formula I in a suitable solvent suchas e.g. dioxane or THF and adding an appropriate amount of thecorresponding acid. The products can usually be isolated by filtrationor by chromatography. The conversion of a compound of formula I into apharmaceutically acceptable salt with a base can be carried out bytreatment of such a compound with such a base. One possible method toform such a salt is e.g. by addition of 1/n equivalents of a basic saltsuch as e.g. M(OH)_(n), wherein M=metal or ammonium cation and n=numberof hydroxide anions, to a solution of the compound in a suitable solvent(e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) andto remove the solvent by evaporation or lyophilization.

Insofar as their preparation is not described in the examples, thecompounds of formula I as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth herein. Starting materials are commercially available, known inthe art or can be prepared by methods known in the art or in analogythereto.

It will be appreciated that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

Pharmacological Tests

The human Via receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds from the present invention tothe human V1a receptor binding studies were performed. Cell membraneswere prepared from HEK293 cells transiently transfected with theexpression vector and grown in 20 liter fermenters with the followingprotocol.

50 g of cells are re-suspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl₂ adjusted to pH=7.4+completecocktail of protease inhibitor (Roche Diagnostics)). Homogenized withPolytron for 1 min and sonicated on ice for 2×2 minutes at 80% intensity(Vibracell sonicator). The preparation is centrifuged 20 min at 500 g at4° C., the pellet is discarded and the supernatant centrifuged 1 hour at43,000 g at 4° C. (19,000 rpm). The pellet is re-suspended in 12.5 mlLysis buffer+12.5 ml Sucrose 20% and homogenized using a Polytron for1-2 min. The protein concentration is determined by the Bradford methodand aliquots are stored at −80° C. until use. For binding studies 60 mgYttrium silicate SPA beads (Amersham) are mixed with an aliquot ofmembrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 10 mM MgCl₂) for 15 minutes with mixing. 50 μl of bead/membranemixture is then added to each well of a 96 well plate, followed by 50 μlof 4 nM 3H-Vasopressin (American Radiolabeled Chemicals). For totalbinding measurement 100 μl of binding buffer are added to the respectivewells, for non-specific binding 100 μl of 8.4 mM cold vasopressin andfor compound testing 100 μl of a serial dilution of each compound in 2%DMSO. The plate is incubated 1 h at room temperature, centrifuged 1 minat 1000 g and counted on a Packard Top-Count. Non-specific bindingcounts are subtracted from each well and data is normalized to themaximum specific binding set at 100%. To calculate an IC 50 the curve isfitted using a non-linear regression model (XLfit) and the Ki iscalculated using the Cheng-Prussoff equation.

The following representative data show the antagonistic activity againsthuman V_(1a) receptor of compounds according to present invention:

TABLE 1 pKi values of selected examples Ex. Structure Name pK_(i)hV_(1a) 1

2′-(1′H,3H-spiro[2-benzofuran-1,4′- piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′- one 9.5 2

1′-(4′-oxo-1,3-dihydro-4′H- spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 9.0 3

2′-(3,3-dimethyl-1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 9.3 4

2′-(4-methyl-1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.2 5

4-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.0 6

5-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.8 7

6-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.8 8

5-methoxy-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.5 9

5-hydroxy-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 9.7 10

6-methoxy-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.6 11

6-hydroxy-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 9.1 12

5,6-dimethoxy-1′-(4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 7.5 13

5,6-dihydroxy-1′-(4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 8.2 14

4-fluoro-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.5 15

5-fluoro-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.9 16

7-fluoro-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.7 17

6-chloro-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.6 18

5-bromo-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.4 19

(−)-2′-(1′H,3H-spiro[2-benzofuran- 1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]- 4′-one 7.6 20

(+)-2′-(1′H,3H-spiro[2-benzofuran- 1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]- 4′-one 6.6 21

5-methyl-2′-(1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 9.1 22

1′-(5-methyl-4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.9 23

(+)-1′-[5-methyl-4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 7.3 24

(−)-1′-[5-methyl-4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 8.6 25

5,6-dimethyl-2′-(1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 7.1 26

1′-(5,6-dimethyl-4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 6.4 27

1′-(5-methoxy-4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 7.7 28

1′-(5-hydroxy-4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.4 29

2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)- 1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one 6.2 30

5-fluoro-2′-(1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 9.0 31

5-chloro-2′-(1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 9.0 32

1′-(5,6-dimethoxy-4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 6.4 33

1′-(5,6-dihydroxy-4′-oxo-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 6.7 34

5,6-difluoro-2′-(1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 9.4 35

1′-(5,6-difluoro-4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′- piperidin]-3-one 8.9 36

2′-(1′H,5H-spiro[furo[3,4- b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.6 37

2′-(1′H,7H-spiro[furo[3,4- b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.0 38

2′-(5,5-dimethyl-1′H,5H- spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H- spiro[indene-2,5′-[1,3]oxazol]-4′-one 9.2 39

2′-(7,7-dimethyl-1′H,7H- spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H- spiro[indene-2,5′-[1,3]oxazol]-4′-one 9.1 40

2′-(7,7-dimethyl-1′H,7H- spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one 8.3 41

2′-(7,7-dimethyl-1′H,7H- spiro[furo[3,4-b]pyridin-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one 8.9 42

2′-(2-methyl-1′H,5H-spiro[furo[3,4- b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 9.1 43

2-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine- 7,4′-piperidin]-5-one 8.3 44

2′-(3-methyl-1′H,5H-spiro[furo[3,4- b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.7 45

3-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine- 7,4′-piperidin]-5-one 7.6 46

2′-(6-methyl-1H,1′H-spiro[furo[3,4- c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.5 47

6-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine- 3,4′-piperidin]-1-one 7.8 48

2′-(2-methyl-1′H,7H-spiro[furo[3,4- b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 7.9 49

2-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine- 5,4′-piperidin]-7-one 7.0 50

2′-(6-methyl-1′H,3H-spiro[furo[3,4- c]pyridine-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.0 51

6-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[furo[3,4-c]pyridine- 1,4′-piperidin]-3-one 7.9 52

2′-(3-methyl-1′H,7H-spiro[furo[3,4- b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′- [1,3]oxazol]-4′-one 8.3 53

3-methyl-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine- 5,4′-piperidin]-7-one 7.4 54

6-chloro-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine- 3,4′-piperidin]-1-one 7.4 55

4-chloro-1′-(4′-oxo-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine- 3,4′-piperidin]-1-one 6.5 56

2′-(1′H,3H-spiro[2-benzofuran-1,4′- piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[b]pyridine-6,5′- [1,3]oxazol]-4′-one 8.2 57

3-(chloromethyl)-2′-(1′H,3H- spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H- spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one 6.3 58

3-methyl-2′-(1′H,3H-spiro[2- benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H- spiro[cyclopenta[c]pyridine-6,5′- [1,3]oxazol]-4′-one7.7 59

3-(fluoromethyl)-2′-(1′H,3H- spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H- spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one 7.6 60

3-(difluoromethyl)-2′-(1′H,3H- spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H- spiro[cylcopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one 7.7 61

2′-(1′H,3H-spiro[2-benzofuran-1,4′- piperidin]-1′-yl)-3-(trifluoromethyl)-5,7-dihydro-4′H- spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one 8.5 62

2′-(1′H,3H-spiro[2-benzofuran-1,4′- piperidin]-1′-yl)-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′- [1,3]oxazol]-4′-one 7.3 63

1′-(4′-oxo-3,4-dihydro-2H,4′H- spiro[naphthalene-1,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2- benzofuran-1,4′-piperidin]-3-one 6.7 64

2′-(1′H,3H-spiro[2-benzofuran-1,4′- piperidin]-1′-yl)-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′- [1,3]oxazol]-4′-one 9.0 65

1′-(4′-oxo-3,4-dihydro-1H,4′H- spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl)-1′H,3H- spiro[2-benzofuran-1,4′- piperidin]-3-one8.8 66

1′-[4′-oxo-3,4-dihydro-1H,4′H- spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H- spiro[2-benzofuran-1,4′- piperidin]-3-oneenantiomer A 9.1 67

1′-[4′-oxo-3,4-dihydro-1H,4′H- spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H- spiro[2-benzofuran-1,4′- piperidin]-3-oneenantiomer B 8.4 68

2′-(7,7-dimethyl-1′H,7H- spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-methyl-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one 8.1 69

2′-(7,7-dimethyl-1′H,7H- spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-hydroxy-1,3- dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one 9.3 70

2′-(7,7-dimethyl-1-oxido-1′H,7H- spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H- spiro[indene-2,5′-[1,3]oxazol]-4′-one 7.3 71

2′-(3-hydroxy-7,7-dimethyl- 1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-4′one 10.2 72

2′-(2-hydroxy-7,7-dimethyl- 1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro- 4′H-spiro[indene-2,5′-[1,3]oxazol]-4′one 8.5

Pharmaceutical Compositions

The compounds of formula I and the pharmaceutically acceptable salts canbe used as therapeutically active substances, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds of formula I and the pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatin capsules. Suitablecarriers for soft gelatin capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like. Depending onthe nature of the active substance no carriers are however usuallyrequired in the case of soft gelatin capsules. Suitable carriers for theproduction of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceuticallyacceptable auxiliary substances such as preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically inert carrier are alsoprovided by the present invention, as is a process for their production,which comprises bringing one or more compounds of formula I and/orpharmaceutically acceptable salts thereof and, if desired, one or moreother therapeutically valuable substances into a galenicaladministration form together with one or more therapeutically inertcarriers.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general formula I orof the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated.

The following examples illustrate the present invention without limitingit, but serve merely as representative thereof. The pharmaceuticalpreparations conveniently contain about 1-500 mg, in particular 1-100mg, of a compound of formula I. Examples of compositions according tothe invention are:

Example A

Tablets of the following composition are manufactured in the usualmanner:

TABLE 2 possible tablet composition mg/tablet ingredient 5 25 100 500Compound of formula I 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 MagnesiumStearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add ingredient 5 and mix for three minutes; compress on a suitablepress.

Example B-1

Capsules of the following composition are manufactured:

TABLE 3 possible capsule ingredient composition mg/capsule ingredient 525 100 500 Compound of formula I 5 25 100 500 Hydrous Lactose 159 123148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 25 Total 200 200 300 600

Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add ingredients 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

The compound of formula I, lactose and corn starch are firstly mixed ina mixer and then in a comminuting machine. The mixture is returned tothe mixer; the talc is added thereto and mixed thoroughly. The mixtureis filled by machine into suitable capsules, e.g. hard gelatin capsules.

Example B-2

Soft Gelatin Capsules of the following composition are manufactured:

TABLE 4 possible soft gelatin capsule ingredient composition ingredientmg/capsule Compound of formula I 5 Yellow wax 8 Hydrogenated Soya beanoil 8 Partially hydrogenated plant oils 34 Soya bean oil 110 Total 165

TABLE 5 possible soft gelatin capsule composition ingredient mg/capsuleGelatin 75 Glycerol 85% 32 Karion 83 8 (dry matter) Titan dioxide 0.4Iron oxide yellow 1.1 Total 116.5

Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example C

Suppositories of the following composition are manufactured:

TABLE 6 possible suppository composition ingredient mg/supp. Compound offormula I 15 Suppository mass 1285 Total 1300

Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered compoundof formula I is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool; the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

Example D

Injection solutions of the following composition are manufactured:

TABLE 7 possible injection solution composition ingredient mg/injectionsolution. Compound of formula I 3 Polyethylene Glycol 400 150 aceticacid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

Manufacturing Procedure

The compound of formula I is dissolved in a mixture of PolyethyleneGlycol 400 and water for injection (part). The pH is adjusted to 5.0 byacetic acid. The volume is adjusted to 1.0 ml by addition of theresidual amount of water. The solution is filtered, filled into vialsusing an appropriate overage and sterilized.

Example E

Sachets of the following composition are manufactured:

TABLE 8 possible sachet composition ingredient mg/sachet Compound offormula I 50 Lactose, fine powder 1015 Microcrystalline cellulose(AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1Total 2500

Manufacturing Procedure

The compound of formula I is mixed with lactose, microcrystallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidone in water. The granulate is mixed withmagnesium stearate and the flavoring additives and filled into sachets.

The following table lists abbreviations used within the presentdocument.

TABLE 9 list with abbreviations AIBN azobisisobutyronitrile brinesaturated sodium chloride solution in water CH₂Cl₂ dichloromethane Cpcyclopentadienyl, C₅H₅ ⁻ cod cyclooctadiene CSO(10-camphorsulfonyl)oxaziridine Cu(OTf)₂ copper(II)trifluoromethanesulfonate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL-Hdiisobutylaluminium hydride DMAP 4-(N,N-dimethylamino)-pyridine DME1,2-dimethoxyethane DMSO dimethylsulfoxide Et₃N triethylamine LDAlithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide MeOHmethanol MS 4A molecular sieves 4Angstrom NaOH sodium hydroxide n-BuOHn-butanol RT room temperature t-BuOK, KOtBu potassium tert-butanolateTFA trifluoroacetic acid THF tetrahydrofuran TMSCN trimethylsilylcyanide TPP triphenylphosphine

Experimental Part

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

Pyridine Intermediates of Formula (XXV)

Pyridine Intermediate 1 (2-Chloro-5-methylpyridin-3-yl)methanol

To a solution of 2-chloro-5-methylnicotinic acid (1.5 g, 8.6 mmol) andtriethylamine (0.92 g, 1.3 ml, 9.1 mmol) in tetrahydrofuran (24 ml) wasadded ethyl chloroformate (0.98 g, 0.87 ml, 9.1 mmol) at 0-5° C. The icebath was removed after 5 minutes and stirring was continued for 1 h. Thesolids were removed by filtration and washed with tetrahydrofuran. Thefiltrate was concentrated in vacuo to give the crude mixed anhydride. Toa solution of lithium aluminum hydride (0.34 g, 9.1 mmol) intetrahydrofuran (18 ml) was added the mixed anhydride from above as asolution in tetrahydrofuran (9 ml) at −78° C. in approximately 20minutes. Stirring was continued for 2 h. The reaction mixture wasquenched by addition of water (0.34 ml), 2 M aqueous sodium hydroxidesolution (0.34 ml) and again water (1.02 ml) at −70° C. The dryice/acetone bath was removed and stirring was continued for 1 h. Theprecipitate was removed by filtration and washed with tetrahydrofuran.The filtrate was concentrated in vacuo to give the title compound (1.1g, 82%) as white solid, which was used in the next step without furtherpurifications. MS m/e: 158 [(M+H)⁺].

Pyridine Intermediate 2 2-(3-Bromopyridin-2-yl)propan-2-ol

To a solution of methyl 3-bromopicolinate (5.0 g, 23 mmol) intetrahydrofuran (116 ml) was added dropwise in approximately 15 minutesmethylmagnesium chloride, 3 M in tetrahydrofuran (16 ml, 49 mmol) at0-5° C. The ice bath was removed after 30 minutes and stirring wascontinued for 1 h. The reaction mixture was quenched with 2 M aqueoushydrogen chloride solution (23 ml, 46 mmol) and stirred for 5 minutes.The solvent was evaporated. The residue was partitioned betweentert-butyl methyl ether (100 ml) and saturated ammonium chloridesolution (100 ml). The layers were separated. The aqueous layer wasextracted with two 100-ml portions of tert-butyl methyl ether. Thecombined organic layers were washed with one 50-ml portion of brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.Flash chromatography with n-heptane/ethyl acetate as eluent gave thetitle compound (4.2 g, 76%) as light yellow oil with a purity of 90%according to NMR. MS m/e: 216, 218 [(M+H)⁺].

Pyridine Intermediate 3 2-(2-Bromopyridin-3-yl)propan-2-ol

To a solution of 2,3-dibromopyridine (5.5 g, 23 mmol) in tetrahydrofuran(77 ml) was added isopropylmagnesium chloride, 2 M in tetrahydrofuran(15 ml, 30 mmol) at room temperature. The reaction mixture was stirredfor 45 minutes. Acetone (2.7 g, 3.4 ml, 46 mmol) was added in a quickfashion at room temperature. The reaction mixture was stirred for 16 hand the quenched with 2 M aqueous hydrogen chloride solution (15 ml).The solvent was evaporated. The residue was partitioned between ethylacetate (100 ml) and water (100 ml). The layers were separated. Theaqueous layer was extracted with one 100-ml portion of ethyl acetate.The combined organic layers were washed with one 50-ml portion ofsaturated ammonium chloride solution, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Flash chromatography withn-heptane/ethyl acetate gave the title compound (2.4 g, 48%) as lightbrown viscous oil. MS m/e: 216, 218 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1 (2H)-carboxylate intermediatesof formula (XXVII) General Procedure I Suzuki Coupling

To a solution of a heteroaromatic compound of formula (XXV), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.1-1.5 eq) and potassium carbonate (3 eq) in 1,2-dimethoxyethane/water(0.2 M, 4:1) is added palladium(II)acetate (0.05 eq) andtriphenylphosphine (0.1 eq). The reaction mixture is heated at 90° C.and stirred for 6-24 h. The reaction mixture is partitioned between anorganic solvent such as ethyl acetate or tert-butyl methyl ether andwater. The layers are separated. The aqueous layer is extracted with oneor two portions of organic solvent. The combined organic layers aredried over anhydrous sodium sulfate, filtered and concentrated todryness. Purification by flash-chromatography gives a tert-butyl4-aryl-5,6-dihydropyridine-1(2H)-carboxylate of formula (XXVII).

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 1 tert-Butyl4-(3-(hydroxymethyl)-5-methylpyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

The title compound was obtained as light yellow viscous oil in 89% yieldaccording to the general procedure XXVII from(2-chloro-5-methylpyridin-3-yl)methanol and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 305 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 2 tert-Butyl4-(2-(2-hydroxypropan-2-yl)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate

The title compound was obtained as colorless viscous oil in 35% yieldaccording to the general procedure I from2-(3-bromopyridin-2-yl)propan-2-ol and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 319 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 3 Methyl2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylnicotinate

The title compound was obtained as light brown oil in 78% yieldaccording to the general procedure I from methyl2-chloro-5-methylnicotinate and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 333 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 4 Methyl3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpicolinate

The title compound was obtained as yellow solid in 74% yield accordingto the general procedure I from methyl 3-bromo-5-methylpicolinate andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 333 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 52-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylnicotinicacid

A mixture of methyl2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylnicotinate(2.5 g, 7.5 mmol) in 1,4-dioxane (38 ml) and 2 M aqueous sodiumhydroxide solution (38 ml, 75 mmol) was stirred for 3 h at roomtemperature. The reaction mixture was partitioned between ethyl acetate(125 ml) and water (10 ml). The layers were separated. The aqueous layerwas acidified by addition of 2 M aqueous hydrochloric acid (38 ml, 75mmol) and extracted with five 125-ml portions of ethyl acetate. Thecombined ethyl acetate layers from the acidic extraction were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was triturated in n-heptane (50 ml) and ethyl acetate (5 ml).The precipitate was collected by filtration, washed with n-heptane anddried in vacuo to give the title compound (1.5 g, 64%) as light yellowsolid. MS m/e: 319 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 63-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpicolinicacid

A solution of methyl3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpicolinate(1.0 g, 3.1 mmol) in 1,4-dioxane (15 ml) and 2 M aqueous sodiumhydroxide solution (15 ml, 31 mmol) was stirred for 2 h at roomtemperature. The reaction mixture was partitioned between isopropylacetate (50 ml) and water (30 ml). The layers were separated. Theaqueous layer was acidified by addition of 2 M aqueous hydrochloric acid(15 ml, 31 mmol) and extracted with five 75-ml portions of ethylacetate. The combined ethyl acetate layers from the acidic extractionwere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was triturated in n-heptane (20 ml) and ethyl acetate(2 ml). The precipitate was collected by filtration, washed withn-heptane and dried in vacuo to give the title compound (1.0 g,quantitative) as white solid. MS m/e: 319 [(M+H)⁺].

tert-Butyl 4-aryl-5,6-dihydropyridine-1(2H)-carboxylate 72-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-6-methylnicotinicacid

The title compound was obtained as white foam in 30% yield according tothe general procedure I from 2-chloro-6-methylnicotinic acid andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 319 [(M+H)⁺].

Iodo-Spiropiperidine Intermediates of Formula (XXVIII) General ProcedureII Cyclization with Iodine and Silver(I)Oxide

To a solution a of tert-butyl4-aryl-5,6-dihydropyridine-1(2H)-carboxylate of formula (XXVII) in1,4-dioxane/water (0.05-0.1 M, 7:1) is added iodine (1.5 eq) at roomtemperature. The reaction mixture is stirred for 30 minutes. Addition ofsilver(I)oxide (1.5 eq) in small portions is followed by stirring for2-16 h. The solids are removed by filtration and washed with a solventsuch as tetrahydrofuran, dioxane or ethyl acetate. The filtrate isconcentrated in vacuo. The residue is partitioned between an organicsolvent such as ethyl acetate or tert-butyl methyl ether and an aqueousinorganic base such as 1 M aqueous sodium carbonate solution. The layersare separated. The aqueous layer is extracted with one or two portionsof organic solvent. The combined organic layers are washed with oneportion of brine (containing 5-10 volume-% aqueous 40% sodium bisulfite)dried over anhydrous sodium sulfate, filtered and concentrated todryness. Purification by flash-chromatography gives aniodo-spiropiperidine of formula (XXVIII).

General Procedure III Cyclization with Iodine and Potassium Iodide

To a solution of a tert-butyl4-aryl-5,6-dihydropyridine-1(2H)-carboxylate of formula (XXVII) inacetonitrile (0.3 M) and 1 M aqueous sodium bicarbonate solution (0.1 M)is added iodine (1.5 eq) and subsequently a 1 M aqueous potassium iodidesolution at room temperature. The reaction mixture is stirred for 2-24 hand then extracted with three portions of an organic solvent such ethylacetate or tert-butyl methyl ether. The combined organic layers arewashed with one portion of brine (containing 5-10 volume-% aqueous 40%sodium bisulfite) dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. Purification by flash-chromatography gives aniodo-spiropiperidine of formula (XXVIII).

Iodo-Spiropiperidine Intermediate 1 tert-Butyl3′-iodo-7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate

The title compound was obtained as light yellow solid in 94% yieldaccording to the general procedure II from tert-butyl4-(2-(2-hydroxypropan-2-yl)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 445 [(M+H)⁺].

Iodo-Spiropiperidine Intermediate 2 tert-Butyl3′-iodo-3-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

The title compound was obtained as off-white solid in 85% yieldaccording to the general procedure III from2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylnicotinicacid. MS m/e: 389 [(M-C₄H)⁺].

Iodo-Spiropiperidine Intermediate 3 tert-Butyl3′-iodo-3-methyl-7-oxo-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate

The title compound was obtained as white solid in 75% yield according tothe general procedure III from3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpicolinicacid. MS m/e: 445 [(M+H)⁺].

Iodo-Spiropiperidine Intermediate 4 tert-Butyl3′-iodo-3-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

The title compound was obtained as white solid in 14% yield according tothe general procedure II from tert-butyl4-(3-(hydroxymethyl)-5-methylpyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.MS m/e: 431 [(M+H)⁺].

Iodo-Spiropiperidine Intermediate 5 tert-Butyl3′-iodo-2-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

The title compound was obtained as white solid in 77% yield according tothe general procedure III from2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-6-methylnicotinicacid. MS m/e: 389 [(M−C₄H₈)⁺].

Spiropiperidine Intermediates of Formula (XXIX) General Procedure IVHydrogenolytic Deiodination

An iodo-spiropiperidine intermediate of formula (XXVIII) (1 eq) isdissolved in a solvent such as ethyl acetate (0.1 M). The flask isevacuated until the solvent begins to bubble gently and back-filled withArgon after 10-30 s. This procedure is repeated twice. After theaddition of an organic base such as triethylamine (1.5 eq) and acatalyst such as palladium, 10% on activated charcoal (0.1-0.5 eq), theflask is evacuated until the solvent begins to bubble and back-filledwith hydrogen. The reaction mixture is stirred under an atmosphere of 1bar of hydrogen gas for 24-72 h. The catalyst is removed by filtrationover Decalite and washed with a solvent such as ethyl acetate. Thefiltrate is concentrated in vacuo. Purification by flash-chromatographygives a spiropiperidine intermediate of formula (XXIX).

General Procedure V Deiodination with Tributyltin Hydride

To a solution of an iodo-spiropiperidine intermediate of formula(XXVIII) (1 eq) and azobisisobutyronitrile (0.05 eq) in toluene (0.1 M)is added dropwise tri-n-butyltin hydride (3 eq) at 85° C. The reactionmixture is stirred for 24-48 h. The reaction mixture is quenched with 1M aqueous potassium fluoride solution (5 eq) at room temperature andstirring is continued for 24 h. The layers are separated. The aqueouslayer is extracted with one portion of toluene. The combined organiclayers are purified by flash-chromatography to give a spiropiperidine offormula (XXIX).

Spiropiperidine Intermediate 1 tert-Butyl3-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate a)tert-Butyl4-hydroxy-4-(2-(hydroxymethyl)-5-methylpyridin-3-yl)piperidine-1-carboxylate

To a suspension of tert-butyl3-methyl-7-oxo-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate(0.51 g, 1.61 mmol) in ethanol (8.0 ml) was added sodium borohydride(0.13 g, 3.53 mmol) in small portions at room temperature. Stirring wascontinued for 6 h. The reaction mixture was quenched with water (6 ml)and partitioned between ethyl acetate (50 ml) and water (30 ml). Thelayers were separated. The aqueous layer was extracted with two 50-mlportions of ethyl acetate. The combined organic layers were washed withone 30-ml portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. Flash chromatography withn-heptane/ethyl acetate gave the title compound (0.38 g, 73%) as whitefoam. MS m/e: 323 [(M+H)⁺].

b) tert-Butyl3-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl4-hydroxy-4-(2-(hydroxymethyl)-5-methylpyridin-3-yl)piperidine-1-carboxylate(0.38 g, 1.2 mmol), 4-(N,N-dimethylamino)-pyridine (0.007 g, 0.059 mmol)and triethylamine (0.35 ml, 2.5 mmol) in tetrahydrofuran (4.7 ml) wasadded methanesulfonyl chloride (0.092 ml, 1.2 mmol) at 0-5° C. The icebath was removed after 5 minutes and stirring was continued for 5 h atroom temperature. The reaction mixture was heated at 50° C. and stirredfor 3 h. The solids were removed by filtration and washed withtetrahydrofuran. Sodium hydride (0.062 g, 1.4 mmol) was added to thefiltrate at 0-5° C. The ice bath was removed and stirring was continuedfor 16 h. The reaction mixture was quenched with water (1 ml) andpartitioned between ethyl acetate (50 ml) and 1 M aqueous sodiumhydroxide solution (30 ml). The layers were separated. The aqueous layerwas extracted with two 50-ml portions of ethyl acetate. The combinedorganic layers were washed with one 30-ml portion of brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Flashchromatography with n-heptane/ethyl acetate gave the title compound(0.21 g, 57%) as white solid. MS m/e: 305 [(M+H)⁺].

Spiropiperidine Intermediate 2 tert-Butyl3-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

The title compound was obtained as colorless viscous oil in 77% yieldaccording to the general procedure V from tert-butyl3′-iodo-3-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 305 [(M+H)⁺].

Spiropiperidine Intermediate 3 tert-Butyl2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate a)tert-Butyl4-hydroxy-4-(2-(hydroxymethyl)-6-methylpyridin-3-yl)piperidine-1-carboxylate

To a solution of lithium aluminum hydride (0.067 g, 1.8 mmol) and intetrahydrofuran (3.6 ml) was added1′-benzyl-2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one(0.54 g, 1.8 mmol) as a solution in tetrahydrofuran (1.8 ml) at 0-5° C.The ice bath was removed after 10 minutes and stirring was continued for15 h. The reaction mixture was quenched by addition of water (0.066 ml),2 M aqueous sodium hydroxide solution (0.066 ml) and again water (0.2ml) at 0-5° C. The reaction mixture was stirred for 2 h. The precipitatewas removed by filtration and washed with tetrahydrofuran. The filtratewas concentrated in vacuo to give a mixture of the N-benzyl- anddes-benzyl-di-ol intermediate. A solution of the mixture anddi-tert-butyl dicarbonate (0.55 g, 2.5 mmol) in ethanol (17 ml) waspurged with Argon. Palladium, 10% on activated charcoal (0.18 g, 0.17mmol) was added. The flask was filled with hydrogen and stirred for 15h. The catalyst was removed by filtration over Decalite and washed withethanol. The filtrate was concentrated in vacuo. Flash chromatographywith n-heptane/isopropanol as eluent gave a di-BOC intermediate mixture.To a solution of di-BOC intermediate mixture in 1,4-dioxane (2 ml) wasadded 4 M hydrogen chloride solution in 1,4-dioxane (2.1 g, 2.0 ml, 8.0mmol) at room temperature. The mixture was stirred overnight. Thesolvent was evaporated. To a suspension of the crude4-(2-(hydroxymethyl)-6-methylpyridin-3-yl)piperidin-4-ol dihydrochloridesalt in dichloromethane (3.6 ml) was added triethylamine (0.45 ml, 3.2mmol) at room temperature. Stirring for 10 minutes was followed byaddition of di-tert-butyl-dicarbonate (0.24 g, 1.1 mmol) at roomtemperature. The reaction mixture was stirred for 15 h at roomtemperature. The reaction mixture was partitioned betweendichloromethane (40 ml) and 1 M aqueous sodium hydroxide solution (20ml). The layers were separated. The aqueous layer was extracted with two40-ml portions of dichloromethane. The combined organic layers werewashed with one 30-ml portion of brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Flash chromatography withn-heptane/isopropanol gave the title compound as white foam (0.14 g,40%). MS m/e: 327.5 [(M+H)⁺].

b) tert-Butyl2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl4-hydroxy-4-(2-(hydroxymethyl)-6-methylpyridin-3-yl)piperidine-1-carboxylate(0.14 g, 0.43 mmol), a catalytic amount 4-(N,N-dimethylamino)-pyridineand triethylamine (0.13 ml, 0.91 mmol) in tetrahydrofuran (2.2 ml) wasadded methanesulfonyl chloride (0.034 ml, 0.43 mmol) at 0-5° C. The icebath was removed after 5 minutes and the reaction mixture was heated to70° C. for 15 h. The reaction mixture was partitioned between ethylacetate (50 ml) and 1 M aqueous sodium hydroxide solution (30 ml). Thelayers were separated. The aqueous layer was extracted with two 50-mlportions of ethyl acetate. The combined organic layers were washed withone 30-ml portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. Flash chromatography withn-heptane/ethyl acetate gave the title compound (0.015 g, 11%) as whitesolid. MS m/e: 305 [(M+H)⁺].

Spiropiperidine Intermediate 4 tert-Butyl2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate a)tert-Butyl4-hydroxy-4-(3-(hydroxymethyl)-6-methylpyridin-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl2-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate(0.36 g, 1.13 mmol) in ethanol (5.7 ml) was added sodium borohydride(0.094 g, 2.49 mmol) in small portions at room temperature. The reactionmixture was stirred for 19 h. The reaction mixture was quenched withwater (3 ml), stirred for 1 h and partitioned between ethyl acetate (40ml) and water (30 ml). The layers were separated. The aqueous layer wasextracted with three 30-ml portions of ethyl acetate. The combinedorganic layers were washed with one 30-ml portion of brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Flashchromatography with n-heptane/ethyl acetate gave the title compound(0.16 g, 43%) as white foam. MS m/e: 323 [(M+H)⁺].

b) tert-Butyl2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl4-hydroxy-4-(3-(hydroxymethyl)-6-methylpyridin-2-yl)piperidine-1-carboxylate(0.15 g, 0.47 mmol), a catalytic amount of4-(N,N-dimethylamino)-pyridine and triethylamine (0.14 ml, 0.99 mmol) intetrahydrofuran (1.9 ml) was added methanesulfonyl chloride (0.037 ml,0.47 mmol) at 0-5° C. The ice bath was removed after 5 minutes andstirring was continued for 2 h at room temperature. The reaction mixturewas partitioned between ethyl acetate (40 ml) and 1 M aqueous sodiumhydroxide solution (30 ml).

The layers were separated. The aqueous layer was extracted with two40-ml portions of ethyl acetate. The combined organic layers were washedwith one 30-ml portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. Flash chromatography withn-heptane/ethyl acetate as eluent gave the title compound (0.1 g, 75%)as white solid. MS m/e: 305 [(M+H)⁺].

Spiropiperidine Intermediate 5 tert-Butyl7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate

The title compound was obtained as off-white solid in 24% yieldaccording to the general procedure IV from tert-butyl3′-iodo-7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate.MS m/e: 319 [(M+H)⁺].

Spiropiperidine Intermediate 6 tert-Butyl3-methyl-7-oxo-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate

The title compound was obtained as white solid in 83% yield according tothe general procedure V from tert-butyl3′-iodo-3-methyl-7-oxo-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate.MS m/e: 319 [(M+H)⁺].

Spiropiperidine Intermediate 7 tert-Butyl2-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

The title compound was obtained as white solid in 95% yield according tothe general procedure V from tert-butyl3′-iodo-2-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 263 [(M-C₄H)⁺].

Spiropiperidine Intermediate 8 tert-Butyl3-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate

The title compound was obtained as white solid in 78% yield according tothe general procedure V from tert-butyl3′-iodo-3-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 263 [(M-C₄Hs)⁺].

N-Benzyl Spiropiperidine Intermediates of Formula (XXXIV) GeneralProcedure VI

To a solution of a halogen carboxylic acid of formula (XXXIII) (1 eq) intetrahydrofuran (0.5 M) is added 1.6 M solution of n-butyllithium (2.05eq) in n-hexane at −78° C. After 5-30 minutes 1-benzylpiperidin-4-one(1.0 eq) is added. The reaction mixture is stirred for 30-60 minutes andthen quenched with 2M aqueous hydrogen chloride solution. The coolingbath is removed and stirring is continued for 1-2 h. The reactionmixture is partitioned between an organic solvent such as ethyl acetateor tert-butyl methyl ether and 0.5 M aqueous sodium hydroxide solution.The layers are separated. The aqueous layer is extracted with one or twoportions of organic solvent. The combined organic layers are dried overanhydrous sodium sulfate, filtered and concentrated to dryness. Thecrude product mixture is dissolved in acetone (0.1-0.3 M) and 4 Mhydrogen chloride solution in 1,4-dioxane (2 eq) is added dropwise atroom temperature. The precipitate is collected by filtration, washedwith acetone and dried in vacuo to give pure spirolactone hydrochloridesalt. The salt is partitioned between an organic solvent such as ethylacetate or tert-butyl methyl ether and 0.5-1.0 aqueous sodium hydroxidesolution. The layers are separated. The aqueous layer is extracted withone or two portions of organic solvent. The combined organic layers aredried over anhydrous sodium sulfate, filtered and concentrated todryness to give a N-benzyl spiropiperidine intermediate of formula(XXXIV).

N-Benzylpiperidine Intermediate 11′-Benzyl-4-methyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one

The title compound was obtained as amorphous colorless solid in 10%yield according to the general procedure VI from 2-bromo-6-methylbenzoicacid and 1-benzylpiperidin-4-one. MS m/e: 308 [(M+H)⁺].

N-Benzylpiperidine Intermediate 21′-Benzyl-5,6-dimethoxy-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white foam in 24% yield according tothe general procedure VI from 2-bromo-4,5-dimethoxybenzoic acid and1-benzylpiperidin-4-one. MS m/e: 354 [(M+H)⁺].

N-Benzylpiperidine Intermediate 31′-Benzyl-2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one

The title compound was obtained as off-white solid in 21% yieldaccording to the general procedure VI from 3-bromo-6-methylpicolinicacid and 1-benzylpiperidin-4-one. MS m/e: 309 [(M+H)⁺].

N-Benzylpiperidine Intermediate 41′-Benzyl-6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 7% yield according tothe general procedure VI from 4-bromo-6-methylnicotinic acid and1-benzylpiperidin-4-one. MS m/e: 310 [(M+H)⁺].

N-Benzylpiperidine Intermediate 51′-Benzyl-6-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one

The title compound was obtained as yellow oil in 11% yield according tothe general procedure VI from 5-bromo-2-chloroisonicotinic acid and1-benzylpiperidin-4-one. MS m/e: 329 [(M+H)⁺].

N-Benzylpiperidine Intermediate 61′-Benzyl-6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one

To a suspension of1′-benzyl-6-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one(0.60 g, 1.0 eq) and tetrakis(triphenylphosphine) palladium (0) (0.021g, 0.01 eq) in tetrahydrofuran (3.1 ml) at 0-5° C., was addeddimethylzinc 2M solution in toluene (0.50 ml, 0.55 eq). The mixture wasstirred at 70° C. for 4 h. The reaction mixture was partitioned betweendichloromethane and aqueous saturated sodium bicarbonate solution. Thelayers were separated. The aqueous layer was extracted withdichloromethane. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The title compoundwas obtained in 87% yield as a brown solid after purification by flashchromatography. MS m/e: 310 ([M+H]⁺).

N-Benzylpiperidine Intermediate 71′-Benzyl-4-methyl-3H-spiro[isobenzofuran-1,4′-piperidine] a)1-Benzyl-4-(2-(hydroxymethyl)-3-methylphenyl)piperidin-4-ol

To a solution of lithium aluminum hydride (0.27 g, 7.2 mmol) intetrahydrofuran (14 ml) was added1′-benzyl-4-methyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one (2.2 g,7.2 mmol) as a solution in tetrahydrofuran (7 ml) at 0-5° C. The icebath was removed after 10 minutes and stirring was continued for 3 d.The reaction mixture was quenched by addition of water (0.27 ml), 2 Maqueous sodium hydroxide solution (0.27 ml) and again water (0.81 ml)and stirred for 1 h. The precipitate was removed by filtration andwashed with tetrahydrofuran. The filtrate was concentrated in vacuo togive the title compound (2.2 g, quantitative) as white solid. MS m/e:312 [(M+H)⁺].

b) 1-Benzyl-4-(2-(chloromethyl)-3-methylphenyl)piperidin-4-ol

To a solution of1-benzyl-4-(2-(hydroxymethyl)-3-methylphenyl)piperidin-4-ol (2.2 g, 7.2mmol), 4-(N,N-dimethylamino)-pyridine (0.044 g, 0.36 mmol) andtriethylamine (12 ml, 15 mmol) in tetrahydrofuran (29 ml) was addedmethanesulfonyl chloride (0.56 ml, 7.2 mmol) at 0-5° C. The ice bath wasremoved after 5 minutes and stirring was continued for 1 h. The reactionmixture was heated at reflux for 15 h. The reaction mixture wasconcentrated in vacuo. The residue was partitioned between ethyl acetate(50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layerswere separated. The aqueous layer was extracted with two 50-ml portionsof ethyl acetate. The combined organic layers were washed with one 30-mlportion of brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Flash chromatography with n-heptane/isopropanolas eluent gave the title compound (1.9 g, 64%) as light yellow viscousoil with a purity of approximately 80% according to NMR. MS m/e: 330[(M+H)⁺].

c) 1′-Benzyl-4-methyl-3H-spiro[isobenzofuran-1,4′-piperidine]

To a mixture of sodium hydride (0.33 g, 6.9 mmol) in tetrahydrofuran (20ml) was added 1-benzyl-4-(2-(chloromethyl)-3-methylphenyl)piperidin-4-ol(1.9 g, 5.7 mmol) as a solution in tetrahydrofuran (5 ml) at 0-5° C. Theice bath was removed and stirring was continued for 20 h. The reactionmixture was quenched with water (1 ml) at 0-5° C. and partitionedbetween ethyl acetate (50 ml) and 0.5 M aqueous sodium hydroxidesolution (50 ml). The layers were separated. The aqueous layer wasextracted with two 50-ml portions of ethyl acetate. The combined organiclayers were washed with one 30-ml portion of brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound (1.8 g, quantitative) as off-white solid. MS m/e: 294 [(M+H)⁺].

N-Benzylpiperidine Intermediate 81′-Benzyl-5,5-dimethyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] a)1-Benzyl-4-(3-(2-hydroxypropan-2-yl)pyridin-2-yl)piperidin-4-ol

To a solution of 2-(2-bromopyridin-3-yl)propan-2-ol (2.4 g, 11 mmol) intetrahydrofuran (37 ml) was added n-butyllithium, 1.6 M in n-hexane (15ml, 23 mmol) at −78° C. The reaction mixture was stirred for 10 minutes.1-Benzylpiperidin-4-one (2.5 g, 13 mmol) was added in a quick fashion asa solution in tetrahydrofuran (5 ml). The dry ice/acetone bath wasremoved after 30 minutes and stirring was continued for 2 h. Thereaction mixture was quenched with water (5 ml) and partitioned betweenethyl acetate (100 ml) and 1 M aqueous sodium hydroxide solution (100ml). The layers were separated. The aqueous layer was extracted with two100-ml portions of ethyl acetate. The combined organic layers werewashed with one 30-ml portion of brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Flash withn-heptane/isopropanol as eluent gave the title compound with a purity of10-20% according to NMR. Purification by Kugelrohr distillation (1-2mbar, 120° C.) gave the title compound (0.58 g, 11%) as brown solid witha purity of approximately 70% according to NMR. MS m/e: 327.5 [(M+H)⁺].

b) 1′-Benzyl-5,5-dimethyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]

To a solution of1-benzyl-4-(3-(2-hydroxypropan-2-yl)pyridin-2-yl)piperidin-4-ol (0.58 g,1.8 mmol) and triethylamine (0.52 ml, 3.8 mmol) in tetrahydrofuran (9.0ml) was added methanesulfonyl chloride (0.15 ml, 1.9 mmol). The reactionmixture was stirred for 2 h at room temperature and for 5 h at reflux.The reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (30 ml). The layers were separated.The aqueous layer was extracted with two 50-ml portions of ethylacetate. The combined organic layers were washed with one 30-ml portionof brine, dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. Flash chromatography with n-heptane/isopropanol gave the titlecompound (0.22 g, 40%) as light brown solid. MS m/e: 309 [(M+H)⁺].

N-Benzylpiperidine Intermediate 91′-Benzyl-6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidine]

To a solution of1′-benzyl-6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one(0.20 g, 1.0 eq) in dichloromethane (7 ml) at −78° C., was addeddiisobutylaluminium hydride (1.3 ml, 2.0 eq). The mixture was stirred at−78° C. for 1 h. Pyridine (0.16 ml, 3.0 eq),4-(N,N-dimethylamino)-pyridine (0.16 g, 2.0 eq) and acetic anhydride(0.37 ml, 6.0 eq) were then added. The mixture was stirred at −78° C.for 12 h then warmed to room temperature. The reaction mixture waspartitioned between 7.5 ml aqueous saturated ammonium chloride and 5 mlsaturated sodium potassium tartrate solution and stirred for 30 minutes.The reaction mixture was poured into aqueous saturated sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting acyl-hemiacetal was used as such inthe next step. To a solution of the acyl-hemiacetal intermediate (0.28g, 1.0 eq) in dichloromethane (10 ml) at room temperature, was addedtriethylsilane (0.95 ml, 7.5 eq) and trifluoroborane diethyl etherate(0.76 ml, 7.5 eq). The mixture was stirred at 40° C. for 25 minutes. Thereaction mixture was partitioned between aqueous saturated sodiumbicarbonate solution and dichloromethane. The aqueous layer wasextracted with dichloromethane. The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thetitle compound was obtained after flash chromatography as white solid in39% yield. MS m/e: 296 ([M+H]⁺).

N-Benzylpiperidine intermediate 101′-Benzyl-6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine]

To a solution of1′-benzyl-6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one(0.20 g, 1.00 eq) in dichloromethane (7 ml) at −78° C., was addeddiisobutylaluminium hydride (1.3 ml, 2.0 eq). The mixture was stirred at−78° C. for 1 h. Pyridine (0.16 ml, 3.0 eq),4-(N,N-dimethylamino)-pyridine (0.16 g, 2.0 eq) and acetic anhydride(0.37 ml, 6.0 eq) were then added. The mixture was stirred at −78° C.for 12 h then warmed to room temperature. The reaction mixture waspartitioned between 7.5 ml aqueous saturated ammonium chloride solutionand 5 ml saturated sodium potassium tartrate solution and stirred for 30minutes. The reaction mixture was poured into aqueous saturated sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting acyl-hemiacetal was filteredthrough a plug of silica and used as such in the next step. To asolution of the acyl-hemiacetal intermediate (0.09 g, 1 eq) indichloromethane (4.7 ml) at room temperature, was added triethylsilane(0.31 ml, 7.5 eq) and trifluoroborane diethyl etherate (0.24 ml, 7.5eq). The mixture was stirred at 40° C. for 12 h. The reaction mixturewas partitioned between 1 M aqueous sodium hydroxide solution anddichloromethane. The aqueous layer was extracted with dichloromethane.The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The title compound was obtainedafter flash chromatography as light yellow oil in 32% yield. MS m/e: 295([M+H]⁺).

Spiropiperidines of Formula (II) General Procedure VII HydrogenolyticN-Debenzylation

An intermediate of formula (XXXIV) or (XXXVII) (1 eq) is dissolved in asolvent such as ethanol (0.1-0.3 M). The flask is evacuated until thesolvent begins to bubble gently and back-filled with Argon after 10-30s. This procedure is repeated twice. After addition of a catalyst suchas palladium, 10% on activated charcoal (0.05-0.1 eq), the flask isevacuated until the solvent begins to bubble and back-filled withhydrogen. The reaction mixture is stirred under an atmosphere of 1 barhydrogen gas for 2-48 h. The catalyst is removed by filtration overDecalite and washed with a solvent. The filtrate is concentrated invacuo to give a spiropiperidine of formula (II).

General Procedure VIII N-BOC Deprotection with Hydrogen Chloride

A solution of an intermediate of formula (XXIX) (1 eq) in 4 M hydrogenchloride solution (10-20 eq HCl) in 1,4-dioxane is stirred for 6-24 h.The reaction mixture is partitioned between 1 M aqueous sodium hydroxidesolution and an organic solvent, e.g. ethyl acetate or dichloromethane.The layers are separated and the aqueous layer is extracted with twoportions of the organic solvent. The combined organic layers are driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a spiropiperidine of formula (II).

General Procedure IX N-BOC Deprotection with Trifluoroacetic Acid

A solution of an intermediate of formula (XXIX) (1 eq) indichloromethane (0.1-1.0 M) and trifluoroacetic acid (10-20 eq) isstirred for 6-24 h. The reaction mixture is partitioned between 1 Maqueous sodium hydroxide solution and an organic solvent, e.g. ethylacetate or dichloromethane. The layers are separated and the aqueouslayer is extracted with two portions of the organic solvent. Thecombined organic layers are dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a spiropiperidine of formula(II).

Spiropiperidine 1 4-Methyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 95% yield according tothe general procedure VII from1′-benzyl-4-methyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one. MS m/e:218 [(M+H)⁺].

Spiropiperidine 25,6-Dimethoxy-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 97% yield according tothe general procedure VII from1′-benzyl-5,6-dimethoxy-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one. MSm/e: 264 [(M+H)⁺].

Spiropiperidine 33-Methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one

The title compound was obtained as white solid in 86% yield according tothe general procedure IX from tert-butyl3-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 219 [(M+H)⁺].

Spiropiperidine 43-Methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one

The title compound was obtained as white solid in 72% yield according tothe general procedure IX from tert-butyl3-methyl-7-oxo-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate.MS m/e: 219 [(M+H)⁺].

Spiropiperidine 52-Methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one

The title compound was obtained as white solid in 73% yield according tothe general procedure IX from tert-butyl2-methyl-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 219 [(M+H)⁺]

Spiropiperidine 62-Methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one

The title compound was obtained as white solid in 95% yield according tothe general procedure VII from1′-benzyl-2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one.MS m/e: 219 [(M+H)⁺].

Spiropiperidine 76-Methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one

The title compound was obtained as yellow oil in quantitative yieldaccording to the general procedure VII from1′-benzyl-6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one.MS m/e: 220 ([M+H]⁺).

Spiropiperidine 86-Methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one

The title compound was obtained as yellow oil in 82% yield according tothe general procedure VII from1′-benzyl-6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one.MS m/e: 219 ([M+H]⁺).

Spiropiperidine 96-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one and4-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one

In a 50 ml round-bottomed flask, 5-bromo-2-chloroisonicotinic acid (1.0g, 4.2 mmol, 1.0 eq) was combined with tetrahydrofuran (18 ml) to give abrown solution. At −78° C., n-butyllithium (1.6 M in hexane, 5.3 ml, 2.0eq) was added within 10 minutes. After 10 minutes stirring at −78° C.,tert-butyl 4-oxopiperidine-1-carboxylate (0.84 g, 1.0 eq) was added. Thereaction mixture was stirred at −78° C. for 30 minutes then warmed toroom temperature. 25 ml water and 25 ml ethyl acetate were added. Thelayers were separated and the aqueous layer was acidified to pH 1 withconcentrated hydrochloric acid. The resulting mixture was stirred at100° C. for 30 minutes. The reaction was cooled down, neutralized withsolid sodium bicarbonate and extracted with ethyl acetate (3×20 ml). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The title compound was obtainedafter purification by flash chromatography in 4% yield containingapproximately 10% of regioisomeric4-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one. MS m/e: 239([M+H]⁺).

Spiropiperidine 10 4-Methyl-3H-spiro[isobenzofuran-1,4′-piperidine]

The title compound was obtained as white solid in 60% yield according tothe general procedure VII from1′-benzyl-4-methyl-3H-spiro[isobenzofuran-1,4′-piperidine]. MS m/e: 204[(M+H)⁺].

Spiropiperidine 113-Methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]

The title compound was obtained as white solid in 88% yield according tothe general procedure IX from tert-butyl3-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate.MS m/e: 205 [(M+H)⁺].

Spiropiperidine 123-Methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]

The title compound was obtained as viscous oil in 88% yield according tothe general procedure IX from tert-butyl3-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 205 [(M+H)⁺].

Spiropiperidine 132-Methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]

The title compound was obtained as colorless oil in 85% yield accordingto the general procedure IX from tert-butyl2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]-1′-carboxylate.MS m/e: 205 [(M+H)⁺].

Spiropiperidine 142-Methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]dihydrochloride

The title compound was obtained as white solid in 95% yield according tothe general procedure VIII from tert-butyl2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate.MS m/e: 205 [(M+H)⁺].

Spiropiperidine 156-Methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidine]

The title compound was obtained as white gum in quantitative yieldaccording to the general procedure VII from1′-benzyl-6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidine. MS m/e:205 ([M+H]⁺).

Spiropiperidine 166-Methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine]

The title compound was obtained as yellow oil in 96% yield according tothe general procedure VII1′-benzyl-6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine. MS m/e:205 ([M+H]⁺).

Spiropiperidine 175,5-Dimethyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]

The title compound was obtained as light brown solid in 85% yieldaccording to the general procedure VII from1′-benzyl-5,5-dimethyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]. MSm/e: 219 [(M+H)⁺].

Spiropiperidine 187,7-Dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]

The title compound was obtained as white solid in 92% yield according tothe general procedure IX from tert-butyl7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-1′-carboxylate.MS m/e: 219 [(M+H)⁺].

Diazoketone Intermediates of Formula (XXIV) General Procedure X

To a solution of an acid chloride intermediate of formula (XXIII) inacetonitrile (0.5 M) is added dropwise 2.0 M solution of trimethylsilyldiazomethane (2.1 eq) in n-hexane at 0-5° C. The ice bath is removedafter 10 minutes and stirring is continued until complete reaction isobserved (2-15 h). Excess trimethylsilyl diazomethane is quenched byslow addition of acetic acid (1 eq) at room temperature. The reactionmixture is concentrated to dryness. Purification by flash-chromatographygives a diazoketone intermediate of formula (XXIV).

Diazoketone 1 1-Diazo-3-(4-methylphenyl)propan-2-one

The title compound was obtained as white solid in 92% yield according tothe general procedure X from p-tolylacetic acid chloride and(trimethylsilyl)-diazomethane. MS m/e: 175 ([M+H]⁺).

Diazoketone 2 1-Diazo-3-(4-methoxyphenyl)propan-2-one

The title compound was obtained as brown oil in quantitative yieldaccording to the general procedure X from 3-methoxyphenylacetic acidchloride and (trimethylsilyl)-diazomethane. MS m/e: 191 ([M+H]⁺).

Diazoketone 3 1-Diazo-3-(3,4-dimethoxyphenyl)propan-2-one

The title compound was obtained as orange liquid according to thegeneral procedure X from 3,4-dimethoxyphenylacetic acid chloride and(trimethylsilyl)-diazomethane. MS m/e: 212 ([M+H]⁺).

Diazoketone 4 1-(2-Chloro-5-methoxyphenyl)-3-diazopropan-2-one

To a solution of 2-(2-chloro-5-methoxyphenyl)acetic acid (5.0 g, 24.9mmol) in dichloromethane (83 ml) were added thionyl chloride (2.73 ml,37.4 mmol) and a catalytic amount of N.N-dimethylformamide at 0-5° C.The cooling bath was removed after 10 minutes, and stirring wascontinued for 16 h. The solvent was evaporated to give the crude2-(2-chloro-5-methoxyphenyl)acetic acid chloride intermediate. The titlecompound was obtained as yellow solid in 63% yield according to thegeneral procedure X from 2-(2-chloro-5-methoxyphenyl)acetic acidchloride and (trimethylsilyl)-diazomethane. MS m/e: 225 ([M+H]⁺).

2-Indanone Intermediates of Formula (XIV) General Procedure XI

To a solution of rhodium (II) acetate dimer (0.01 eq) in dichloromethane(0.002 M) is added a solution of a diazoketone intermediate of formula(XXIV) in dichloromethane (0.2 M) dropwise at 0-5° C. The reactionmixture is concentrated to dryness. Purification by flash-chromatographyor Kugelrohr distillation gives a 2-indanone intermediate of formula(XIV).

2-Indanone Intermediate 1 5-Methyl-1,3-dihydro-2H-inden-2-one

The title compound was obtained as off-white solid in 29% yieldaccording to the general procedure XI from1-diazo-3-(4-methylphenyl)propan-2-one. MS m/e: 146 (M+).

2-Indanone Intermediate 2 5-Methoxy-1,3-dihydro-2H-inden-2-one

The title compound was obtained as off-white solid in 29% yieldaccording to the general procedure XI from1-diazo-3-(3-methoxyphenyl)propan-2-one. MS m/e: 163 ([M−H]⁺).

2-Indanone intermediate 3 5,6-Dimethoxy-1H-inden-2(3H)-one

The title compound was obtained as orange semi-solid in 45% yieldaccording to the general procedure XI from1-diazo-3-(3,4-dimethoxyphenyl)propan-2-one. MS m/e: 192 ([M]⁺).

2-Indanone Intermediate 4 5,6-Difluoro-1,3-dihydro-2H-inden-2-one

To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-2-ol (2.6 g, 16 mmol)in dichloromethane (54 ml) was added Dess-Martin periodinane (8.5 g, 20mmol) at room temperature. The reaction mixture was stirred for 7 h.Diethyl ether (250 ml) was added to the reaction mixture and stirringwas continued for 15 minutes. The precipitate was removed by filtrationand washed with diethyl ether. The filtrate was washed with one 150-mlportion of saturated aqueous saturated bicarbonate solution. The layerswere separated. The aqueous layer was extracted with two 150-ml portionsof diethyl ether. The combined organic layers were washed with one150-ml portion of brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. Flash-chromatography with n-heptane/ethylacetate gave the title compound (1.8 g, 69%) as white solid. MS m/e: 167([M−H]⁻).

2-Indanone Intermediate 5 4-Chloro-7-methoxy-1H-inden-2(3H)-one

The title compound was obtained as light yellow solid in 21% yieldaccording to the general procedure XI from1-(2-chloro-5-methoxyphenyl)-3-diazopropan-2-one. MS m/e: 195([M−H)⁻]⁻).

Cyanohydrin Intermediates of Formula (XV) and Trimethylsilyl CyanohydrinIntermediates of Formula (XVI) General Procedure XV Copper Catalyzed

A solution of a 2-indanone intermediate of formula (XIV), trimethylsilylcyanide (2.6 eq) and copper(II) trifluoromethanesulfonate (0.01 eq) indichloromethane (0.5-1.0 M) is stirred at room temperature for 15-24 h.The reaction mixture is concentrated to dryness to give a trimethylsilylcyanohydrin intermediate of formula (XVI). The crude compound of formula(XVI) is partitioned between an organic solvent such as dichloromethaneand water. The layers are separated. The aqueous layer is extracted withone or two portions of organic solvent. The combined organic layers arewashed with one portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated to dryness to give an intermediate of formula(XVI). During the work-up the trimethylsilyl group of the resultingtrimethylsilyl cyanohydrin may be partially or completely cleaved togive a cyanohydrin intermediate of formula (XV).

General Procedure XVI Lanthanum Catalyzed

A solution of a 2-indanone intermediate of formula (XIV),2-hydroxy-2-methylpropanenitrile (1.5 eq) and lanthanum(III)isopropoxide (0.1 eq) in tetrahydrofuran (0.5-1.0 M) is stirred at roomtemperature for 15-24 h. The reaction mixture is partitioned between anorganic solvent such as ethyl acetate or tert-butyl methyl ether andsaturated aqueous ammonium chloride solution. The layers are separated.The aqueous layer is extracted with one or two portions of organicsolvent. The combined organic layers are washed with one portion ofbrine, dried over anhydrous sodium sulfate, filtered and concentrated todryness. Purification by flash-chromatography gives a cyanohydrinintermediate of formula (XV).

Cyanohydrin 12-[(Trimethylsilyl)oxy]-2,3-dihydro-1H-indene-2-carbonitrile

The title compound was obtained as light brown oil in quantitative yieldaccording to the general procedure XV from 2-indanone and trimethylsilylcyanide. MS m/e: 231 (M+)

Cyanohydrin 25-Methyl-2-[(trimethylsilyl)oxy]-2,3-dihydro-1H-indene-2-carbonitrile

The title compound was obtained as yellow oil in 95% yield according tothe general procedure XV from 5-methyl-1,3-dihydro-2H-inden-2-one andtrimethylsilyl cyanide.

Cyanohydrin 35-Methoxy-2-[(trimethylsilyl)oxy]-2,3-dihydro-1H-indene-2-carbonitrile

The title compound was obtained as brown oil in 97% yield according tothe general procedure XV from 5-methoxy-1,3-dihydro-2H-inden-2-one andtrimethylsilyl cyanide. MS m/e: 261 (M+).

Cyanohydrin 45,6-Difluoro-2-[(trimethylsilyl)oxy]-2,3-dihydro-1H-indene-2-carbonitrile

The title compound was obtained as yellow oil in 66% yield with a purityof approximately 70% (by NMR) according to the general procedure XV from5,6-difluoro-1,3-dihydro-2H-inden-2-one and trimethylsilyl cyanide.

Cyanohydrin 55,6-Dimethoxy-2-(trimethylsilyloxy)-2,3-dihydro-1H-indene-2-carbonitrile

The title compound was obtained as dark red oil in 100% yield accordingto the general procedure XV from 5,6-dimethoxy-1H-inden-2(3H)-one andtrimethylsilyl cyanide. MS m/e: 291 ([M+]⁺).

Cyanohydrin 6 1-(Trimethylsilyloxy)-2,3-dihydro-1H-indene-1-carbonitrile

The title compound was obtained as yellow oil in 74% yield according tothe general procedure XV from 2,3-dihydro-1H-inden-1-one andtrimethylsilyl cyanide.

Cyanohydrin 7 2-Hydroxy-1,2,3,4-tetrahydronaphthalene-2-carbonitrile

The title compound was obtained as light brown oil in 20% yieldaccording to the general procedure XVI from3,4-dihydronaphthalen-2(1H)-one and 2-hydroxy-2-methylpropanenitrile.

Cyanohydrin 81-(Trimethylsilyloxy)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

The title compound was obtained as yellow oil in 72% yield according tothe general procedure XVI from 3,4-dihydronaphthalen-1(2H)-one,trimethylsilanecarbonitrile and copper(II) trifluoromethanesulfonate. MSm/e: 246 ([M+H]⁺).

Cyanohydrin 94-Chloro-7-methoxy-2-(trimethylsilyloxy)-2,3-dihydro-1H-indene-2-carbonitrile

The title compound was obtained as brown oil in quantitative yieldaccording to the general procedure XV from4-chloro-7-methoxy-1H-inden-2(3H)-one and trimethylsilyl cyanide.

Malonic Acid Ester Intermediates of Formula (XX) General Procedure XII

To a mixture of sodium hydride (2.1 eq) in tetrahydrofuran (1.0 M) isadded a malonate derivative (1.1 eq) of formula (XVIII). The reactionmixture is stirred for 1 h. A solution of an alkylating reagent (1.0 eq)of formula (XIX) is added dropwise as a solution in tetrahydrofuran (1.0M). The reaction mixture is stirred for 1-24 h and then quenched withsaturated aqueous ammonium chloride solution at room temperature. Thereaction mixture is partitioned between an organic solvent such as ethylacetate or tert-butyl methyl ether and saturated aqueous ammoniumchloride solution. The layers are separated. The aqueous layer isextracted with one or two portions of organic solvent. The combinedorganic layers are washed with one portion of brine, dried overanhydrous sodium sulfate, filtered and concentrated to dryness.Purification by flash-chromatography gives an intermediate of formula(XX).

Malonic Acid Ester Intermediate 1 2-tert-Butyl 2-ethyl5,6-dimethyl-1H-indene-2,2(3H)-dicarboxylate

The title compound was obtained as colorless oil in 86% yield from1,2-bis(chloromethyl)-4,5-dimethylbenzene and tert-butyl ethyl malonateaccording to the general procedure XII. MS m/e: 263 ([M-C₄H]⁺).

Malonic Acid Intermediates of Formula (XXI) General Procedure XIII

To a solution of a compound of formula (XX) in a solvent suchdichloromethane (0.1-0.5 M) is added trifluoro acetic acid (10-20 eq) at0-5° C. The cooling bath is removed after 10-30 minutes and stirring iscontinued for 16-24 h. The reaction mixture is partitioned between anorganic solvent such as ethyl acetate or dichloromethane and saturatedaqueous ammonium chloride solution. The layers are separated. Theaqueous layer is extracted with one or two portions of organic solvent.The combined organic layers are washed with one portion of brine, driedover anhydrous sodium sulfate, filtered and concentrated to dryness togive a compound of formula (XXI).

Malonic Acid 12-(Ethoxycarbonyl)-5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylic acid

The title compound was obtained as grey solid in 95% yield from2-tert-butyl 2-ethyl 5,6-dimethyl-1H-indene-2,2(3H)-dicarboxylateaccording to the general procedure XIII. MS m/e: 261 ([M−H]⁻).

2-Indanecarboxvlic Ester Intermediates of Formula (XXII) GeneralProcedure XIV

A solution of a compound of formula (XXI), lithium chloride (2.1 eq) andwater (1.05 eq) in dimethyl sulfoxide (0.5 M) is stirred at 180° C. for6 h. The reaction mixture is partitioned between an organic solvent suchas ethyl acetate or tert-butyl methyl ether and 0.5 M aqueous hydrogenchloride solution. The layers are separated. The aqueous layer isextracted with one or two portions of organic solvent. The combinedorganic layers are washed with one portion of brine, dried overanhydrous sodium sulfate, filtered and concentrated to dryness. Asolution of the crude reaction mixture in an alcohol such as ethanol ormethanol is stirred at reflux with a catalytic amount of sulfuric acidfor 6-24 h. The reaction mixture is concentrated to dryness.Purification by flash-chromatography gives an intermediate of formula(XXII).

2-Indanecarboxylic ester 1 Ethyl5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylate

The title compound was obtained as light brown oil in 85% yield from2-(ethoxycarbonyl)-5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylic acidaccording to the general procedure XIV. MS m/e: 218 ([M]⁺).

Alpha-Hydroxy Ester Intermediates of Formula (XII) and (XVII) GeneralProcedure XVII Cyanohydrin Hydrolysis with Aqueous Hydrogen Chloride

A solution of a cyanohydrin intermediate of formula (XV) or atrimethylsilyl cyanohydrin intermediate of formula (XVI) in an alcoholsuch as methanol or ethanol (0.3 M) and concentrated hydrochloric acid(20 eq) is refluxed for 6-24 h. The reaction mixture is partitionedbetween an organic solvent such as ethyl acetate or tert-butyl methylether and water. The layers are separated. The aqueous layer isextracted with one or two portions of organic solvent. The combinedorganic layers are washed with one portion of brine, dried overanhydrous sodium sulfate, filtered and concentrated to dryness.Purification by flash-chromatography gives an alpha-hydroxy esterintermediate of formula (XII).

General Procedure XVIII Pinner-Type Cyanohydrin Hydrolysis

A solution of a cyanohydrin intermediate of formula (XV) or atrimethylsilyl cyanohydrin intermediate of formula (XVI) and an alcoholsuch as methanol or ethanol (1 eq) in 4 M hydrochloric acid in1,4-dioxane (4-10 eq) is stored overnight in the freezer oralternatively stirred over night at −10 to −5° C. Water is added to thereaction mixture and stirring is continued for 1-4 h. The reactionmixture is partitioned between an organic solvent such as ethyl acetateor tert-butyl methyl ether and water. The layers are separated. Theaqueous layer is extracted with one or two portions of organic solvent.The combined organic layers are washed with one portion of brine, driedover anhydrous sodium sulfate, filtered and concentrated to dryness.Purification by flash-chromatography gives an alpha-hydroxy esterintermediate of formula (XII).

General Procedure XIX Alpha-Hydroxylation of 2-Indanecarboxylic Esters

To a solution of an 2-indanecarboxylic ester intermediate of formula(XXII) in tetrahydrofuran (0.5-1.0 M) is added 1.0 M lithiumbis(trimethylsilyl)amide solution in tetrahydrofuran (1.1 eq) at −78° C.The cooling bath is removed and stirring is continued for 45 minutes at0-5° C. A solution of (1S)-(+)-(10-camphorsulfonyl)oxaziridine (1.05 eq)as a solution in tetrahydrofuran (0.65 M) is added at max −55° C. Thereaction mixture is stirred for 1-2 h. The cooling bath is removed andthe reaction mixture is quenched by addition of saturated aqueousammonium chloride solution at −20° C. The reaction mixture ispartitioned between an organic solvent such as ethyl acetate ortert-butyl methyl ether and 0.5 M aqueous hydrogen chloride solution.The layers are separated. The aqueous layer is extracted with one or twoportions of organic solvent. The combined organic layers are washed withone portion of brine, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. Purification by flash-chromatography gives analpha-hydroxy ester intermediate of formula (XII).

Alpha-Hydroxy Ester 1 Ethyl2-hydroxy-2,3-dihydro-1H-indene-2-carboxylate a)2-Hydroxy-2,3-dihydro-1H-indene-2-carboxylate

A slurry of 2-(trimethylsilyloxy)-2,3-dihydro-1H-indene-2-carbonitrile(21.0 g, 90.8 mmol) and concentrated hydrochloric acid (75.6 ml, 908mmol) was stirred for 1 h at room temperature and for 4 h at 100° C. Thereaction mixture was diluted with one 50-ml portion of water. Theheating bath was removed and stirring was continued for 15 h. Theprecipitate was collected by filtration and washed with two 50-mlportions of 1 M aqueous hydrogen chloride solution. The wet precipitatewas partitioned between ethyl acetate (150 ml) and 1 M aqueous sodiumhydroxide solution (150 ml). The layers were separated. The organiclayer was extracted with two 200-ml portions of 0.5 M aqueous sodiumhydroxide solution. The combined aqueous layers were extracted with one150-ml portion of ethyl acetate. The combined aqueous layers wereacidified by addition of concentrated hydrochloric acid (35 ml). Theaqueous layer was extracted with two 150-ml portions of ethyl acetate.The combined ethyl acetate layers from the acidic extraction were washedwith one 50-ml portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was triturated indiethyl ether (100 ml) for 3 h at room temperature. The precipitate wascollected by filtration, washed with diethyl ether and dried in vacuo togive the title compound as off-white solid. Crystallization from hotethyl acetate (90 ml) afforded the title compound (7.0 g, 43%) as whitesolid. MS m/e: 177 ([M−H]⁻).

b) Ethyl 2-hydroxy-2,3-dihydro-1H-indene-2-carboxylate

To a solution of 2-hydroxy-2,3-dihydro-1H-indene-2-carboxylic acid (4.0g, 22.4 mmol) in ethanol (74.8 ml) was added a catalytic amount (3drops) of sulfuric acid at room temperature. The reaction mixture wasstirred for 48 h. The solvent was evaporated in vacuo. The residue waspartitioned between ethyl acetate (150 ml) and 1 M sodium carbonate (50ml). The layers were separated. The organic layer was washed with one50-ml portion of brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give the title compound (4.5 g, 97%) aswhite solid.

Alpha-Hydroxy Ester 2 Ethyl2-hydroxy-5-methoxy-2,3-dihydro-1H-indene-2-carboxylate a)2-Hydroxy-5-methoxy-2,3-dihydro-1H-indene-2-carboxylate

A solution of5-methoxy-2-(trimethylsilyloxy)-2,3-dihydro-1H-indene-2-carbonitrile(4.98 g, 19.1 mmol) in toluene (12 ml) was added dropwise at 85-90° C.to a vigorously stirred solution of aqueous hydrochloride acid 25% (13.9g, 12.4 ml, 95.3 mmol). The reaction mixture was stirred for 20 h andwas then allowed to cool to room temperature. The mixture waspartitioned between isopropyl acetate (50 ml) and water (30 ml). Thelayers were separated. The aqueous layer was extracted with two 50-mlportions of isopropyl acetate. The combined organic layers were washedwith one 30-ml portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was triturated indiethyl ether (50 ml). The solids were removed by filtration and washedwith diethyl ether. The filtrate was concentrated in vacuo. The residuewas partitioned between tert-butyl methyl ether (50 ml) and 1 M aqueoussodium hydroxide solution (50 ml). The layers were separated. Theorganic layer was extracted with two 50-ml portions of 1 M aqueoussodium hydroxide solution. The aqueous layer was extracted with one100-ml portion of tert-butyl methyl ether. The combined aqueous layerswere acidified by addition of 80 ml 2 M aqueous hydrogen chloridesolution and extracted with three 50-ml portions of ethyl acetate. Thecombined ethyl acetate layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. Flash-chromatography withn-heptane/2-propanol gave the title compound (2.37 g, 60%) as brownsolid. MS m/e: 207 ([M−H]⁻).

b) Ethyl 2-hydroxy-5-methoxy-2,3-dihydro-1H-indene-2-carboxylate

To a solution of 2-hydroxy-5-methoxy-2,3-dihydro-1H-indene-2-carboxylicacid (2.32 g, 11.1 mmol) in ethanol (37.1 ml) was added a catalyticamount of sulfuric acid. The reaction mixture was stirred for 15 h atroom temperature. The solvent was evaporated in vacuo. The residue waspartitioned between ethyl acetate (50 ml) and 1 M sodium carbonate (50ml). The layers were separated. The aqueous layer was extracted withthree 50-ml portion of ethyl acetate. The combined organic layers werewashed with one 30-ml portion of brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Flash chromatography withn-heptane/ethyl acetate as eluent gave the title compound (1.57 g, 60%)a light yellow viscous oil. MS m/e: 237 ([M+H]+).

Alpha-Hydroxy Ester 3 Methyl2-hydroxy-5-methyl-2,3-dihydro-1H-indene-2-carboxylate

The title compound was obtained as brown oil in 45% yield according tothe general procedure XVII from5-methyl-2-[(trimethylsilyl)oxy]-2,3-dihydro-1H-indene-2-carbonitrile.

Alpha-Hydroxy Ester 4 Ethyl2-hydroxy-5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylate

The title compound was obtained as yellow oil in 30% yield according tothe general procedure XIX from ethyl5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylate.

Alpha-Hydroxy Ester 5 Methyl5,6-difluoro-2-hydroxy-2,3-dihydro-1H-indene-2-carboxylate

The title compound was obtained as light brown solid in 46% yieldaccording to the general procedure XVII from5,6-difluoro-2-[(trimethylsilyl)oxy]-2,3-dihydro-1H-indene-2-carbonitrile.

Alpha-Hydroxy Ester 6 Methyl2-hydroxy-5,6-dimethoxy-2,3-dihydro-1H-indene-2-carboxylate

The title compound was obtained as orange solid in 35% yield accordingto the general procedure XVIII from5,6-dimethoxy-2-(trimethylsilyloxy)-2,3-dihydro-1H-indene-2-carbonitrile.

Alpha-Hydroxy Ester 7 Methyl1-hydroxy-2,3-dihydro-1H-indene-1-carboxylate

The title compound was obtained as brown oil in 91% yield according tothe general procedures XVIII from1-(trimethylsilyloxy)-2,3-dihydro-1H-indene-1-carbonitrile. MS m/e: 193([M+H]⁺).

Alpha-Hydroxy Ester 8 Methyl2-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate

The title compound was obtained as colorless oil in 84% yield accordingto the general procedure XVIII from2-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carbonitrile.

Alpha-Hydroxy Ester 9 Methyl1-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate

The title compound was obtained as yellow oil in 87% yield according tothe general procedure XVIII from1-(trimethylsilyloxy)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile.

Alpha-Hydroxy Ester 10 Ethyl4-chloro-2-hydroxy-7-methoxy-2,3-dihydro-1H-indene-2-carboxylate

To a solution of 4-chloro-7-methoxy-2-(trimethylsilyloxy)-2,3-dihydro-1H-indene-2-carbonitrile (1.01 g, 3.41 mmol) intoluene (6.9 ml) was added hydrochloric acid, 25% in water (2.22 ml,17.1 mmol) at 90° C. The reaction mixture was stirred for 15 h. Theheating bath was removed, and stirring was continued for 2 h. Thereaction mixture was partitioned between ethyl acetate (50 ml) and brine(20 ml). The layers were separated. The aqueous layer was extracted withtwo 50-ml portions of ethyl acetate. The combined organic layers werewashed with one 20-ml portion of brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the crudealpha-hydroxy acid intermediate (1.3 g, dark brown). A mixture of thealpha-hydroxy acid intermediate in ethanol (14 ml) and a catalyticamount of sulfuric acid was stirred at room temperature for 6 h. Thesolvent was evaporated in vacuo. The residue was partitioned betweenethyl acetate (50 ml) and 1 M aqueous sodium bicarbonate solution (50ml). The layers were separated. The aqueous layer was extracted with two50-ml portion of ethyl acetate. The combined organic layers were washedwith one 30-ml portion of brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification by flash-chromatography withn-heptane/ethyl acetate as eluent gave the title compound (0.169 g, 18%)as brown viscous oil. MS m/e: 270 ([M]⁺).

Alpha-Hydroxy Ester 11 Ethyl2-hydroxy-7-methoxy-2,3-dihydro-1H-indene-2-carboxylate

A 50-ml two-necked round-bottomed flask was charged with ethyl4-chloro-2-hydroxy-7-methoxy-2,3-dihydro-1H-indene-2-carboxylate (0.169g, 0.624 mmol) and ethanol (6.2 ml). The flask was evacuated toapproximately 110 mbar until the solvent began to bubble gently andback-filled with Argon after 10 s. This procedure was repeated twice.After addition of palladium, 10% on activated charcoal (133 mg, 125μmol, Eq: 0.2), the flask was evacuated to 110 mbar, back-filled withhydrogen and stirred for 20 h under an atmosphere of 1 bar of hydrogengas. The catalyst was removed by filtration over Decalite and washedwith ethanol. The solvent was evaporated. The residue was partitionedbetween ethyl acetate (50 ml) and water/brine (1:1) (30 ml). The layerswere separated. The aqueous layer was extracted with two 50-ml portionsof ethyl acetate. The combined organic layers were washed with one 20-mlportion of brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound (0.147 g, quantitative)as light brown viscous oil. MS m/e: 236 ([M]⁺).

2-Amino-oxazol-4-one intermediates of formula (III) General Procedure XX

A mixture of molecular sieves 4A, guanidine hydrochloride (1.6-7 eq) andpotassium tert-butoxide in tert-butanol is stirred at room temperaturefor 2-24 h. Addition of an alpha-hydroxy ester intermediate of formula(XII) is followed by stirring for 2-24 h. The reaction mixture isdiluted with a solvent mixture such as ethyl acetate/2-propanol (4:1) orisopropyl acetate/2-propanol (4:1). The solids are removed byfiltration. The filtrate is washed with water. The layers are separated.The aqueous layer is extracted with one or two portions of organicsolvent mixture. The combined organic layers are washed with one portionof brine, dried over anhydrous sodium sulfate, filtered and concentratedto dryness. Trituration from a solvent such as ethyl acetate orisopropyl acetate gives a 2-amino-oxazol-4-one intermediate of formula(III).

2-Amino-oxazol-4-one intermediate 12′-Amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 75% yield according tothe general procedure XX from ethyl2-hydroxy-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 203 ([M+H]⁺).

2-Amino-oxazol-4-one intermediate 22′-Amino-5-methyl-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 86% yieldaccording to the general procedure XX from ethyl2-hydroxy-5-methyl-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 217([M+H]⁺).

2-Amino-oxazol-4-one intermediate 32′-Amino-5,6-dimethyl-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one

The title compound was obtained off-white solid in quantitative yieldaccording to the general procedure XX from ethyl2-hydroxy-5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 231([M+H]⁺).

2-Amino-oxazol-4-one intermediate 42′-Amino-5,6-difluoro-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained white solid in 73% yield according tothe general procedure XX from ethyl2-hydroxy-5,6-dimethyl-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 239([M+H]⁺).

2-Amino-oxazol-4-one intermediate 52′-Amino-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained white solid in 68% yield according tothe general procedure XX from ethyl2-hydroxy-5-methoxy-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 233([M+H]⁺).

2-Amino-oxazol-4-one intermediate 62′-Amino-5,6-dimethoxy-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one

The title compound was obtained as light brown solid in 35% yieldaccording to the general procedure XX from methyl2-hydroxy-5,6-dimethoxy-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 264([M+H]⁺).

2-Amino-oxazol-4-one intermediate 72′-Amino-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one

The title compound was obtained as brown solid in 85% yield according tothe general procedure XX from methyl1-hydroxy-2,3-dihydro-1H-indene-1-carboxylate. MS m/e: 203 ([M+H]⁺).

2-Amino-oxazol-4-one intermediate 82′-Amino-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 71% yieldaccording to the general procedure XX from methyl2-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate.

2-Amino-oxazol-4-one intermediate 92′-Amino-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 61% yieldaccording to the general procedure XX from methyl1-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate. MS m/e: 217([M+H]⁺).

2-Amino-oxazol-4-one intermediate 102′-Amino-4-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one

The title compound was obtained as off-white solid in 69% yieldaccording to the general procedure XX from ethyl2-hydroxy-4-methoxy-2,3-dihydro-1H-indene-2-carboxylate. MS m/e: 233([M+H]⁺).

Intermediate of Formula (V)2-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one

To a solution of 3H-spiro[isobenzofuran-1,4′-piperidine] (7.9 g, 42mmol) in dichloromethane (250 ml), 2-chloroacetyl isocyanate (5.0 g,41.8 mmol) was added at RT. The mixture was stirred at 22° C. for 1 h.The reaction progress was monitored by LC/MS. The reaction mixture waspoured into 250 ml water and extracted with dichloromethane (2×200 ml).The organic layers were dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was dissolved withtetrahydrofuran (500 ml) to give a colorless solution.1,8-Diazabicyclo[5.4.0]undec-7-ene (13 ml, 83 mmol) was added. Thereaction mixture was stirred at RT for 30 minutes. The reaction mixturewas poured into 400 ml aqueous 1 M hydrogen chloride and extracted withethyl acetate (1×500 ml) and dichloromethane (2×300 ml). The organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The light yellow solid crude was purified byprecipitation from dichloromethane with ethyl acetate yielding the titlecompound (5.7 g, 50% yield) as a white solid. MS m/e: 273 ([M+H]⁺).

Intermediate of Formula (VIII)5,5-Di(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-one

To a solution of2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-one (4.0g, 15 mmol, 1.0 eq) in tetrahydrofuran (107 ml) was added lithiumbis(trimethylsilyl)amide (29 ml, 29 mmol, 2.0 eq) at −78° C. The mixturewas allowed to warm at −30° C. After 30 minutes 3-bromoprop-1-yne (4.9ml, 44 mmol, 3.0 eq) was added at −78° C. The cooling bath was removedand the mixture was allowed to warm to room temperature. The reactionmixture was poured into 25 ml 1 M aqueous hydrogen chloride solution andextracted with three 25-ml portions of dichloromethane. The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification by flash-chromatography withn-heptane/ethyl acetate as eluent gave the title compound (2.7 g, 52%)as yellow solid. MS m/e: 349 ([M+H]⁺).

Intermediate of Formula (VII)5-(Prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-one

In a schlenk-tube,2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-one (5.0g, 18 mmol, 1.0 eq) was dissolved in tetrahydrofuran (183 ml) andlithium bis(trimethylsily)amide (18 ml, 18 mmol, 1.0 eq) was addedslowly at −30° C. and stirred for 1 h. The Li-intermediate was added toa solution of 3-bromoprop-1-yne in (5.5 g, 4.1 ml, 37 mmol, 2.0 eq) intetrahydrofuran (33 ml) at 0-5° C. Stirring was continued for 30minutes. The reaction mixture was poured into 10 ml 1 M aqueous hydrogenchloride solution and extracted with three 10-ml portions ofdichloromethane. The combined organic layers were dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification by flashchromatography with n-heptane/ethyl acetate as eluent gave the titlecompound (1.3 g, 22%) as light brown solid. MS m/e: 311 ([M+H]⁺).

Intermediate of formula (XI)2-(4-Oxo-5-(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)-4,5-dihydrooxazol-5-yl)acetonitrile

To a solution of5-(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-one(0.10 g, 0.32 mmol, 1.0 eq) in tetrahydrofuran (3 ml) was added lithiumbis(trimethylsilyl)amide (0.39 ml, 0.39 mmol, 1.2 eq) at −78° C.Stirring was continued for 5 minutes, then 2-bromoacetonitrile (0.034ml, 0.48 mmol, 1.5 eq) was added. The reaction mixture was allowed towarm to room temperature and was quenched by the addition of 10 mlaqueous saturated ammonium chloride solution and extracted with two20-ml portions of dichloromethane. The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.Purification by flash chromatography with n-heptane/ethyl acetate aseluent gave the title compound (0.042 g, 37%) as light brown solid. MSm/e: 350 ([M+H]⁺).

EXAMPLES General Procedure XXI Aminolysis

A mixture of a spiropiperidine of formula (II) as free base and a2-amino-oxazol-4-one intermediate of formula (III) in a solvent such asethanol, n-butanol, tert-butanol, 1,4-dioxane or tetrahydrofuran(0.1-0.3 M) is heated at 78-125° C. for 6-72 h. Alternatively a mixtureof a spiropiperidine of formula (II) as hydrochloride salt (1-1.5 eq),an organic base such as Huenig's Base or triethylamine (1-1.5 eq) and a2-amino-oxazol-4-one intermediate of formula (III) in a solvent such asethanol, n-butanol, tert-butanol, 1,4-dioxane or tetrahydrofuran(0.1-0.3 M) is heated at 78-125° C. for 6-72 h. The mixture canalternatively be heated under microwave irradiation at 130-160° C. for10-30 minutes. After cooling to room temperature the reaction mixture ispartitioned between an organic solvent such as ethyl acetate ordichloromethane and aqueous saturated ammonium chloride solution. Thelayers are separated. The aqueous layer is extracted with one or twoportions of organic solvent. The combined organic layers are washed withone portion of brine, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. Purification by flash-chromatography orcrystallization from a suitable solvent gives a compound of formula (I).

General Procedure XXII Ruthenium Catalyzed 2+2+2 Cyclization

To a solution of a compound of formula (VII) in 1,2-dichloroehtane (0.2M) is added an alkyne intermediate of formula (IX) (1.5 eq) at roomtemperature.Chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) (0.03eq) is added as a solution in 1,2-dichloroethane. The reaction mixtureis stirred for 20-60 minutes and consecutively concentrated to dryness.Purification by flash-chromatography gives a compound of formula (I).

General Procedure XXIII Cobalt Catalyzed 2+2+2 Cyclization

A solution of a compound of formula (XI) in toluene (0.04 M) andcyclopentadienecobalt dicarbonyl (0.3 eq) is purged with ethyne threetimes and positive pressure is maintained at 1.5 bar. The vessel isplaced in front of a 300 W tungsten lamp (approximately 5 cm) andirradiated for 1 h. During the reaction, the temperature rises toapproximately 80° C. and the pressure increases to 2.5 bar. The reactionmixture is concentrated to dryness. Purification by flash-chromatographygives a compound of formula (I).

Example 12′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white foam in 28% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3H-spiro[isobenzofuran-1,4′-piperidine]according to the generalprocedure XXI. MS m/e: 375 ([M+H]⁺).

Example 21′-(4′-Oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as light-brown solid in 44% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to the generalprocedure XXI. MS m/e: 390 ([M+H]⁺).

Example 32′-(3,3-Dimethyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light-brown solid in 23% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3,3-dimethyl-3H-spiro[isobenzofuran-1,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 403 ([M+H]⁺).

Example 42′-(4-Methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 52% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and4-methyl-3H-spiro[isobenzofuran-1,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 389.5 ([M+H]⁺).

Example 54-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as light brown solid in 55% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and4-methyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 403 ([M+H]⁺).

Example 65-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

In a 5 ml pear-shaped flask,5-bromo-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(50 mg, 1.0 eq) and tetrakis(triphenylphosphine)palladium (0) (6.2 mg,0.050 eq) were combined with tetrahydrofuran (1 ml) to give a brownsuspension. Dimethylzinc, 2 M in toluene (0.054 ml, 1.0 eq) was added.The reaction mixture was heated to 70° C. and stirred for 4 h. Thereaction mixture was poured into 2 ml 5% sodium carbonate solution andextracted with ethyl acetate (3×5 ml). The organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography yielding the titlecompound in 65% yield as off white solid. MS m/e: 403 ([M+H]⁺).

Example 76-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

In a 5 ml microwave vial,6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(50 mg, 1.0 eq) and methylboronic acid (11 mg, 1.5 eq) were combinedwith toluene (0.5 ml) to give a brown suspension. Palladium (II) acetate(0.53 mg, 0.02 eq), potassium phosphate monohydrate (55 mg, 2.0 eq) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.9 mg, 0.04 eq)were added. The reaction mixture was heated to 90° C. and stirred for 4h. The reaction mixture was poured into 2 ml 5% sodium carbonatesolution and extracted with ethyl acetate (3×5 ml). The organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography yieldingthe title compound in 8% yield. MS m/e: 403 ([M+H]⁺).

Example 85-Methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 25% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and5-methoxy-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 419 ([M+H]⁺).

Example 95-Hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

To a solution of5-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(0.013 g, 0.031 mmol) in dichloromethane (2.0 ml) was added borontribromide, 1 M in dichloromethane (0.093 ml, 0.093 mmol) at −78° C. Thereaction mixture was stirred for 1 h. The dry ice/acetone bath wasremoved and stirring was continued for 30 minutes. Further borontribromide, 1 M in dichloromethane (0.093 ml, 0.093 mmol) was added at0-5° C. The reaction mixture was stirred for 30 minutes. The ice bathwas removed and stirring was continued for 15 h. The reaction mixturewas quenched with ice water and partitioned between dichloromethane (30ml) and saturated aqueous bicarbonate solution (10 ml). The layers wereseparated. The aqueous layer was extracted with three 10-ml portions ofdichloromethane. The combined organic layers were washed with one 5-mlportion of brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Purification by preparative RP-HPLC on a GeminiNX 3u 50×4.6 mm column with methanol/water as eluent gave the titlecompound (0.005 g, 40%) as off-white solid. MS m/e: 405 ([M+H]⁺).

Example 106-Methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as off-white solid in 74% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and6-methoxy-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 419 ([M+H]⁺).

Example 116-Hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

To a suspension of6-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(60 mg, 1.0 eq) in dichloromethane (0.72 ml) at 0-5° C., was added 1 Mboron tribromide solution in dichloromethane (0.43 ml, 3.0 eq). Themixture was stirred at 0-5° C. for 2 h, then at 22° C. for 18 h. Thereaction mixture was quenched with water and stirred for 15 minutes,then dichloromethane was added. The phases were separated. The aqueouslayer was extracted with dichloromethane (2×5 ml). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The title compound was obtainedafter purification by flash chromatography in 26% yield as a whitesolid. MS m/e: 406 ([M+H]⁺).

Example 125,6-Dimethoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 53% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and5,6-dimethoxy-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according tothe general procedure XXI. MS m/e: 449 ([M+H]⁺).

Example 135,6-Dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

To a solution of5,6-dimethoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(0.22 g, 0.48 mmol) in dichloromethane (2.4 ml) was added 1 M borontribromide solution in dichloromethane (1.4 ml, 1.4 mmol) at 0-5° C. Thereaction mixture was stirred for 10 minutes at 0-5° C. The ice bath wasremoved and stirring was continued at room temperature for 3 h. Thereaction mixture was quenched with ice/water at 0-5° C. and stirred for5 minutes. The solvent was evaporated. The residue was partitionedbetween ethyl acetate (50 ml) and water (10 ml). The layers wereseparated. The aqueous layer was extracted with three 50-ml portions ofethyl acetate. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Purification bypreparative RP-HPLC on a Gemini NX 3u 50×4.6 mm column withmethanol/water as eluent gave the title compound (0.007 g, 3%) as redsolid. MS m/e: 421 ([M+H]⁺).

Example 144-Fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white gum in 19% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and4-fluoro-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 407 ([M+H]⁺).

Example 155-Fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 17% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and5-fluoro-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 407 ([M+H]⁺).

Example 167-Fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as off-white solid in 51% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and7-fluoro-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 407 ([M+H]⁺).

Example 176-Chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as brown foam in 47% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and6-chloro-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 423 ([M+H]⁺).

Example 185-Bromo-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as light brown foam in 20% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and5-bromo-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 469 ([M+H]⁺).

Example 19(−)-2′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-oneand Example 20(+)-2′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one

The title compounds were obtained according to the general procedure XXIfrom 2′-amino-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one and3H-spiro[isobenzofuran-1,4′-piperidine] following chiral HPLC separationon a Chiralpak AD column with n-heptane/ethanol as eluent. The compoundsare cited in the order of elution:

(−)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one:off-white solid, 7% yield. MS m/e: 375 ([M+H]⁺).

(+)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one:light yellow solid, 8% yield. MS m/e: 375 ([M+H]⁺).

Example 215-Methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 62% yield from2′-amino-5-methyl-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one and3H-spiro[isobenzofuran-1,4′-piperidine] according to the generalprocedure XXI. MS m/e: 389 ([M+H]⁺).

Example 221′-(5-Methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as off-white solid in 74% yield from2′-amino-5-methyl-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one and3H-spiro[isobenzofuran-1,4′-piperidin]-3-one hydrochloride usingtriethylamine according to the general procedure XXI. MS m/e: 403([M+H]⁺).

Example 23(+)-1′-[5-Methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneand Example 24(−)-1′-[5-Methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

(+)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneand(−)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-onewere obtained from1′-(5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneby chiral HPLC separation on Lux Amylose column with n-heptane/ethanolas eluent.

(+)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(0.050 g, 27%) was obtained as white solid. MS m/e: 403.5 ([M+H]⁺).[α]D=+23.10 (c=1.000, CHCl₃, 20° C.).

(−)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(0.049 g, 26%) was obtained as white solid. MS m/e: 403.5 ([M+H]⁺).[α]D=−21.00 (c=1.000, CHCl₃, 20° C.).

Example 255,6-Dimethyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 38% yield from2′-amino-5,6-dimethyl-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidine] according to the generalprocedure XXI. MS m/e: 403 ([M+H]⁺).

Example 261′-(5,6-Dimethyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 12% yield from2′-amino-5,6-dimethyl-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one hydrochloride usingtriethylamine according to the general procedure XXI. MS m/e: 417([M+H]⁺).

Example 271′-(5-Methoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 48% yield from2′-amino-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one and3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to the generalprocedure XXI. MS m/e: 419 ([M+H]⁺).

Example 281′-(5-Hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

To a solution of1′-(5-methoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(0.27 g, 0.65 mmol) in dichloromethane (6.5 ml) was added 1 M borontribromide solution in dichloromethane (1.9 ml, 1.9 mmol) at 0-5° C. Theice bath was removed after 5 minutes and stirring was continued for 1 h.The reaction mixture was quenched with methanol (1 ml) at 0-5° C. andstirred for 5 minutes. The reaction mixture was partitioned betweenethyl acetate (50 ml) and saturated bicarbonate solution (30 ml). Thelayers were separated. The aqueous layer was extracted with two 50-mlportions of ethyl acetate. The combined organic layers were washed withone 30-ml portion of brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was triturated in warmethyl acetate (6 ml). The precipitate was collected by filtration,washed with ethyl acetate and dried in vacuo to give the title compound(0.23 g, 90%) as off-white solid. MS m/e: 405 ([M+H]⁺).

Example 292′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 48% yield from5,5-di(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-oneand trimethylsilylacetylene usingchloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) as acatalyst according to the general procedure XXII. MS m/e: 447 ([M+H]⁺).

Example 305-Fluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

In a 10 ml round-bottomed flask,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one(30 mg, 1.0 eq) and boron trifluoride diethyl etherate (1.90 g, 200 eq)were combined to give a yellow solution. Mercuric acetate (2.1 mg, 0.1eq) and lead tetraacetate (36 mg, 1.2 eq) were added and the reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas poured into 20 ml aqueous saturated sodium bicarbonate solution andextracted with dichloromethane (4×25 ml). The organic layers were driedover magnesium sulfate, filtered and concentrated in vacuo. The titlecompound was obtained after flash chromatography as a light brown solidin 80% yield. MS m/e: 393 ([M+H]⁺).

Example 315-Chloro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

In a 5 ml round-bottomed flask,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one(45 mg, 1.0 eq) and tert-butyl hypochlorite (16 mg, 1.5 eq) werecombined with dichloromethane (1 ml) to give a light yellow solution.The mixture was stirred at room temperature for 5 h and thenconcentrated in vacuo. The title compound was obtained as colorless oilafter purification by HPLC in 18% yield. MS m/e: 410 ([M+H]⁺).

Example 321′-(5,6-Dimethoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 5% yield from2′-amino-5,6-dimethoxy-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 449 ([M+H]⁺).

Example 331′-(5,6-Dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

To a suspension of1′-(5,6-dimethoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(0.064 g, 1.0 eq) in dichloromethane (0.72 ml) at 0-5° C., was added 1 Mboron tribromide solution in dichloromethane (0.43 ml, 3.0 eq). Themixture was stirred at 0-5° C. for 2 h. The reaction mixture wasquenched with water and stirred for 15 minutes, then dichloromethane wasadded. The phases were separated. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The title compound was obtained by flash chromatography as light brownsolid in 13% yield. 421 ([M+H]⁺).

Example 345,6-Difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 10% yield from2′-amino-5,6-difluoro-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidine] according to the generalprocedure XXI. MS m/e: 411 ([M+H]⁺).

Example 351′-(5,6-Difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as white solid in 5% yield from2′-amino-5,6-difluoro-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one hydrochloride usingtriethylamine according to the general procedure XXI. MS m/e: 425([M+H]⁺).

Example 362′-(1′H,5H-Spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as colorless oil in 4% yield accordingto the general procedure XXI from5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]hydrochloride, and2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one usingHuenig's Base. MS m/e: 376.5 ([M+H]⁺).

Example 372′-(1′H,7H-Spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 25% yield according tothe general procedure XXI from7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine] and2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one. MS m/e:376 ([M+H]⁺).

Example 382′-(5,5-Dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 25% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and5,5-dimethyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] according tothe general procedure XXI. MS m/e: 404 ([M+H]⁺).

Example 392′-(7,7-Dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 23% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine] according tothe general procedure XXI. MS m/e: 404 ([M+H]⁺).

Example 402′-(7,7-Dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 47% yield from2′-amino-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one and7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine] according tothe general procedure XXI. MS m/e: 434 ([M+H]⁺).

Example 412′-(7,7-Dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

To a solution of2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one(0.27 g, 0.62 mmol) in dichloromethane (6.2 ml) was added 1 M borontribromide solution in dichloromethane (1.9 ml, 1.9 mmol) at 0-5° C. Theice bath was removed after 5 minutes and stirring was continued for 1 h.The reaction mixture was quenched with methanol (1 ml) at 0-5° C. andstirred for 5 minutes.

The reaction mixture was partitioned between ethyl acetate (50 ml) andsaturated bicarbonate solution (30 ml). The layers were separated. Theaqueous layer was extracted with two 50-ml portions of ethyl acetate.The combined organic layers were washed with one 30-ml portion of brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was triturated in warm ethyl acetate (6 ml). The precipitatewas collected by filtration, washed with ethyl acetate and dried invacuo to give the title compound (0.24 g, 93%) as off-white solid. MSm/e: 420 ([M+H]⁺).

Example 422′-(2-Methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white foam in 49% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 390 ([M+H]⁺).

Example 432-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one

The title compound was obtained as off-white solid in 46% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one according tothe general procedure XXI. MS m/e: 404 ([M+H]⁺).

Example 442′-(3-Methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 46% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 390 ([M+H]⁺).

Example 453-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one

The title compound was obtained as light yellow solid in 28% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one according tothe general procedure XXI. MS m/e: 404 ([M+H]⁺).

Example 462′-(6-Methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 56% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 391 ([M+H]⁺).

Example 476-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one

The title compound was obtained as brown solid in 16% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and6-methyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one according tothe general procedure XXI. MS m/e: 405 ([M+H]⁺).

Example 482′-(2-Methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 41% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]dihydrochlorideusing Huenig's Base according to the general procedure XXI. MS m/e:390.5 ([M+H]⁺).

Example 492-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one

The title compound was obtained as light brown solid in 16% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and2-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one according tothe general procedure XXI. MS m/e: 404 ([M+H]⁺).

Example 502′-(6-Methyl-1′H,3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 16% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 391 ([M+H]⁺).

Example 516-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one

The title compound was obtained as light brown solid in 15% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and6-methyl-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one according tothe general procedure XXI. MS m/e: 405 ([M+H]⁺).

Example 522′-(3-Methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 27% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine] according to thegeneral procedure XXI. MS m/e: 390 ([M+H]⁺).

Example 533-Methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one

The title compound was obtained as white solid in 54% yield from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and3-methyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one according tothe general procedure XXI. MS m/e: 404 ([M+H]⁺).

Example 546-Chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-oneExample 554-Chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one

The title compounds were obtained from2′-amino-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one and amixture of 6-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-oneand 4-chloro-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-oneaccording to the general procedure XXI. Purification by HPLC yielded:

6-Chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one:light brown solid, 12% yield. MS m/e: 424 ([M+H]⁺).

4-Chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one:light brown solid, 1% yield. MS m/e: 424 ([M+H]⁺).

Example 562′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[b]pyridine-6,5′-[1,3]oxazol]-4′-one

The title compound was obtained as colorless oil in 4% yield from2-(4-oxo-5-(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)-4,5-dihydrooxazol-5-yl)acetonitrileand ethyne using cylopentadienylcobalt dicarbonyl as a catalystaccording to the general procedure XXIII. MS m/e: 376 ([M+H]⁺).

Example 573-(Chloromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 54% yield from5,5-di(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-oneand 2-chloroacetonitrile usingchloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) as acatalyst according to the general procedure XXII. MS m/e: 424 ([M+H]⁺).

Example 583-Methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one

In a 25 ml round-bottomed flask,3-(chloromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-(0.03g, 1 eq) and sodium acetate (0.015 g, 2.5 eq) were combined withmethanol (3 ml) to give a light brown suspension. Palladium 10% oncharcoal (0.023 g, 0.3 eq) was added. Hydrogen gas was bubbled throughthe reaction mixture for 5 minutes, and stirring was continued for 1 hunder an atmosphere of 1 bar of hydrogen gas. The reaction mixture wasfiltered through a plug of celite and concentrated in vacuo. The titlecompound was obtained by flash chromatography as a light brown solid in44% yield. MS m/e: 390 ([M+H]⁺).

Example 593-(Fluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown oil in 28% yield from5,5-di(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-oneand 2-fluoroacetonitrile usingchloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) as acatalyst according to the general procedure XXII. MS m/e: 408 ([M+H]⁺).

Example 603-(Difluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light yellow solid in 85% yield from5,5-di(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-oneand 2,2-difluoroacetonitrile usingchloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) as acatalyst according to the general procedure XXII. MS m/e: 426 ([M+H]⁺).

Example 612′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3-(trifluoromethyl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 1% yield from5,5-di(prop-2-ynyl)-2-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-yl)oxazol-4(5H)-oneand 2,2,2-trifluoroacetonitrile usingchloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) as acatalyst according to the general procedure XXII. MS m/e: 444 ([M+H]⁺).

Example 622′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-one

The title compound was obtained as light brown solid in 3%2′-amino-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidin]according to the generalprocedure XXI. MS m/e: 390 ([M+H]⁺)

Example 631′-(4′-Oxo-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as light yellow solid in 3% from2′-amino-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure XXI. MS m/e: 403 ([M+H]⁺).

Example 642′-(1′H,3H-Spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as white solid in 9% yield from3H-spiro[isobenzofuran-1,4′-piperidine] and2′-amino-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-oxazol]-4′-oneaccording to the general procedure XXI. MS m/e: 388 ([M+H]⁺).

Example 65 1′-(4′-Oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl)-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The title compound was obtained as off-white solid in 37% from2′-amino-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-oneand 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one according to thegeneral procedure according to the general procedure XXI. MS m/e: 403([M+H]⁺)

Example 661′-[4′-Oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer A and Example 671′-[4′-Oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′1,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer B

1′-[4′-Oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer A and1′-[4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer B were obtained from 1′-(4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl)-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneby chiral HPLC separation on a Reprosil Chiral-NR column withn-heptane/ethanol as eluent. The compounds are cited in the order ofelution:

1′-[4′-Oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer A (0.011 g, 11%) was obtained as off-white powder. MS m/e:403 ([M+H]⁺).

1′-[4′-Oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer B (0.011 g, 11%) was obtained as off-white powder. MS m/e:403 ([M+H]⁺).

Example 682′-(7,7-Dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

The title compound was obtained as off-white solid in 41% yield from2′-amino-4-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-oxazol]-4′-one and7,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine] according tothe general procedure XXI. MS m/e: 434 ([M+H]⁺).

Example 692′-(7,7-Dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

To a solution of2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one(0.066 g, 0.152 mmol) in dichloromethane (1.5 ml) was added 1M borontribromide solution in dichloromethane (0.457 ml, 0.457 mmol) at 0-5° C.The ice bath was removed after 5 minutes, and stirring was continued for5 min. The excess boron tribromide was quenched with methanol (0.25 ml)at 0-5° C. and stirred for 5 minutes. The reaction mixture waspartitioned between ethyl acetate (50 ml) and saturated aqueous sodiumbicarbonate solution (25 ml). The layers were separated. The aqueouslayer was extracted with two 40-ml portions of ethyl acetate. Thecombined organic layers were washed with one 25-ml portion of brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.Crystallization from ethyl acetate (1 ml) gave the title compound (0.041g, 64%) as off-white solid. MS m/e: 420 ([M+H]⁺).

Example 702′-(7,7-Dimethyl-1-oxido-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

To a mixture of2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one(0.300 g, 0.744 mmol) in dichloromethane (7.44 ml) was addedm-chloroperbenzoic acid (0.192 g, 1.12 mmol). Stirring was continued for72 h. The reaction mixture was partitioned between dichloromethane (30ml) and saturated bicarbonate solution (30 ml). The layers wereseparated. The aqueous layer was extracted with three 30-ml portions ofdichloromethane. The combined organic layers were washed with one 30-mlportion of brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Purification by preparative RP-HPLC on a GeminiNX 3u 50×4.6 mm column with water/acetonitrile/triethylamine gave thetitle compound (0.20 g, 65%) as white solid. MS m/e: 420 ([M+H]⁺).

Example 712′-(3-Hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-oneand Example 722′-(2-Hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-onea)7,7-Dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-3-ylacetate and7,7-dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-2-ylacetate

A solution of2′-(7,7-dimethyl-1-oxido-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one(0.140 g, 0.334 mol) and 2,4,6-trimethylpyridine (0.089 ml, 0.668 mmol)in acetic anhydride (3.15 ml, 33.4 mmol) was heated at 140° C. andstirred for 15 h. The reaction mixture was partitioned between ethylacetate (50 ml) and saturated bicarbonate solution (75 ml). The layerswere separated. The aqueous layer was extracted with two 50-ml portionsof ethyl acetate. The combined organic layers were washed with one 30-mlportion of saturated ammonium chloride solution, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Purification bypreparative RP-HPLC on a Gemini 5 um C18 100×30 mm column withwater/acetonitrile/formic acid gave7,7-dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-3-ylacetate and7,7-dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-2-ylacetate.

7,7-Dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-3-ylacetate was obtained as off-white solid in 6% yield. MS m/e: 462([M+H]⁺).

7,7-Dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-2-ylacetate was obtained as off-white solid in 10% yield. MS m/e: 462([M+H]⁺).

b)2′-(3-Hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

To a solution of7,7-dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-3-ylacetate (0.010 g, 0.0217 mmol) in methanol (1 ml) was added 5.4 M sodiummethoxide solution in methanol (0.000401 ml, 2.17 μmol, Eq: 0.0999).Stirring was continued for 30 minutes. The reaction mixture waspartitioned between dichloromethane (20 ml) and saturated ammoniumchloride solution (10 ml). The layers were separated. The aqueous layerwas extracted with three 20-ml portions of dichloromethane. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the crude title compound (0.009 g, 99%) asoff-white solid. MS m/e: 420 ([M+H]⁺).

c)2′-(2-Hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one

To a solution of7,7-dimethyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-oxazole]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]-2-ylacetate (0.015 g, 0.0325 mmol) in methanol (1 ml) was added sodiummethoxide (0.000602 ml, 0.00325 mmol). Stirring was continued for 30minutes. The reaction mixture was partitioned between dichloromethane(20 ml) and saturated ammonium chloride solution (10 ml). The layerswere separated. The aqueous layer was extracted with three 20-mlportions of dichloromethane. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thecrude title compound (0.012 g, 88%). MS m/e: 420 ([M+H]⁺)

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1. A compound of formula I,

wherein X¹ is C—R¹ or N; X² is C—R¹ or N; X³ is C—R¹ or N; X⁴ is C—R¹ orN; whereby only one of X¹, X², X³ and X⁴ is N; R¹ each separately isselected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₆-alkyl and C₁₋₆-alkoxy; R² is selected from the group consisting ofH and C₁₋₆-alkyl; R³ is selected from the group consisting of H andC₁₋₆-alkyl; or R² and R³ together are ═O; Y¹ is C—R⁴ or N; Y² is C—R⁴ orN; Y³ is C—R⁴ or N; Y⁴ is C—R⁴ or N; whereby only one of Y¹, Y², Y³ andY⁴ is N; R⁴ each separately is selected from the group consisting ofhydrogen, halogen, halogen-C₁₋₆-alkyl, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxyand Si(C₁₋₆-alkyl)₃; m is 1, 2 or 3; and n is 0 or 1; orpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,wherein X¹ is C—H or N; X² is C—R¹ or N; X³ is C—R¹; X⁴ is C—H or N;whereby only one of X¹, X², X³ and X⁴ is N; R¹ each separately isselected from the group consisting of hydrogen, halogen, hydroxy, andC₁₋₆-alkyl; R² is selected from the group consisting of H andC₁₋₆-alkyl; R³ is selected from the group consisting of H andC₁₋₆-alkyl; or R² and R³ together are ═O; Y¹ is C—H or N; Y² is C—R⁴ orN; Y³ is C—R⁴ or N; Y⁴ is C—H or N; whereby only one of Y¹, Y², Y³ andY⁴ is N; R⁴ each separately is selected from the group consisting ofhydrogen, halogen, hydroxy and C₁₋₆-alkyl; m is 1; and n is
 1. 3. Thecompound of claim 1, wherein X¹, X², X³ and X⁴ are each CH; R² and R³are each H; m and n are each 1; Y¹ and Y⁴ are each CH; and Y² and Y³ areeach CF.
 4. The compound of claim 1, wherein X¹, X² and X³ are each CHand X⁴ is N; R² and R³ are each C₁₋₆-alkyl; m and n are each 1; and Y¹,Y², Y³ and Y⁴ are each CH.
 5. The compound of claim 1, wherein, X¹ isC—R¹; X² is C—R¹; X³ is C—R¹; X⁴ is NO; R¹ each separately is selectedfrom the group consisting of hydrogen, halogen, hydroxy, C₁₋₆-alkyl andC₁₋₆-alkoxy; R² is selected from the group consisting of H andC₁₋₆-alkyl; R³ is selected from the group consisting of H andC₁₋₆-alkyl; or R² and R³ together are ═O; Y¹ is C—R⁴ or N; Y² is C—R⁴ orN; Y³ is C—R⁴ or N; Y⁴ is C—R⁴ or N; wherein only one of Y¹, Y², Y³ andY⁴ is N; R⁴ each separately is selected from the group consisting ofhydrogen, halogen, halogen-C₁₋₆-alkyl, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxyand Si(C₁₋₆-alkyl)₃; m is 1, 2 or 3; and n is 0 or 1; orpharmaceutically acceptable salts thereof.
 6. The compound of claim 5,wherein X¹, X² and X³ are each CH and X⁴ is NO; R² and R³ are eachC₁₋₆-alkyl; m and n are each 1; and Y¹, Y², Y³ and Y⁴ are each CH. 7.The compound of claim 5, wherein X¹, X² and X³ are each CH and X⁴ is NO;R² and R³ are each H; m and n are each 1; and Y¹, Y², Y³ and Y⁴ are eachCH.
 8. The compound of claim 1, selected from the group consisting of(1R)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,(1S)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[,3]oxazol]-2′-yl)-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(4′-oxo-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dimethoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dimethyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-methoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-[(2R)-4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-[(2R)-5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-[(2S)-4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-[(2S)-5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3-(trifluoromethyl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[b]pyridine-6,5′-[1,3]oxazol]-4′-one,2′-(2-hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(2-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(2-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3,3-dimethyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-hydroxy-7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(4-methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(5,5-dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(6-methyl-1′H,3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-4-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1-oxido-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,2′-spiro[5H-furo[3,4-b]pyridine-7,4′-piperidine]-1′-ylspiro[indane-2,5′-oxazole]-4′-one,2′-spiro[7H-furo[3,4-b]pyridine-5,4′-piperidine]-1′-ylspiro[indane-2,5′-oxazole]-4′-one,3-(chloromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,3-(difluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,3-(fluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,3-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,4-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,4-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,4-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5,6-dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5,6-dimethoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5,6-dimethyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5-bromo-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-chloro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-fluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,6-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one,and7-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one.9. The compound of claim 1, selected from the group consisting of(+)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,(−)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2,3-dihydro-4′H-spiro[indene-1,5′-[1,3]oxazol]-4′-one,1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl)-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(4′-oxo-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dimethoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dimethyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-methoxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-[4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer A,1′-[4′-oxo-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-2′-yl]-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-3-oneenantiomer B,(−)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,(+)-1′-[5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3-(trifluoromethyl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-2H,4′H-spiro[naphthalene-1,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-3,4-dihydro-1H,4′H-spiro[naphthalene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(trimethylsilyl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[b]pyridine-6,5′-[1,3]oxazol]-4′-one,2′-(2-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(2-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3,3-dimethyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(4-methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(5,5-dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(6-methyl-1′H,3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-methoxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,2-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,2′-(1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,3-(chloromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,3-(difluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,3-(fluoromethyl)-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,3-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5,7-dihydro-4′H-spiro[cyclopenta[c]pyridine-6,5′-[1,3]oxazol]-4′-one,4-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,4-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,4-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5,6-dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5,6-dimethoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5,6-dimethyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5-bromo-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-chloro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-fluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-methyl-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-chloro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,6-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-methoxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one,6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[furo[3,4-c]pyridine-1,4′-piperidin]-3-one,and7-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one.10. The compound of claim 1, selected from the group consisting of1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-difluoro-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5,6-dihydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-(5-hydroxy-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,1′-[(2R)-5-methyl-4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(5,5-dimethyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-5-hydroxy-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-one,3-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one,5,6-difluoro-2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,5,6-dihydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-fluoro-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,5-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,6-hydroxy-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,and6-methyl-1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1-one.11. The compound of claim 1, selected from the group consisting of2′-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,1′-(4′-oxo-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-2′-yl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,2′-(6-methyl-1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,2′-(3-methyl-1′H,5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,and2′-(3-methyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one.12. The compound2′-(7,7-dimethyl-1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-yl)-1,3-dihydro-4′H-spiro[indene-2,5′-[1,3]oxazol]-4′-one,or a pharmaceutically acceptable salt thereof.
 13. A process tomanufacture a compound of formula I, comprising the step of reacting acompound of formula (II)

with a compound of formula (III)

wherein n, m, R², R³, X¹⁻⁴ and Y¹⁻⁴ are as defined hereinabove forformula (I).
 14. (canceled)
 15. (canceled)
 16. (canceled)
 17. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier and/or a pharmaceutically acceptableauxiliary substance.
 18. (canceled)
 19. A method for treating conditionsof inappropriate secretion of vasopressin, anxiety, depressivedisorders, obsessive compulsive disorder, autistic spectrum disorders,schizophrenia, aggressive behavior and phase shift sleep disorders, inparticular jetlag, which method comprises administering said compound ofclaim 1 to a human being or animal.
 20. (canceled)